Diamine derivatives

ABSTRACT

The present invention relates to diamine compounds which inhibit activated blood coagulation factor X and exhibit an anticoagulant effect and there uses for treating various diseases based on thromboembolism.

TECHNICAL FIELD

The present invention relates to novel compounds which inhibit activatedblood coagulation factor X (hereinafter abbreviated as “FXa”) to exhibita potent anticoagulant effect and can be orally administered, andanticoagulants or agents for preventing and/or treating thrombosis orembolism, which comprise such a novel compound as an active ingredient.

BACKGROUND ART

In unstable angina, cerebral infarction, cerebral embolism, myocardialinfarction, pulmonary infarction, pulmonary embolism, Buerger's disease,deep venous thrombosis, disseminated intravascular coagulation syndrome,thrombus formation after valve replacement, reocclusion afterangioplasty and thrombus formation during extracorporeal circulation,hypercoagulable state is a pivotal factor. Therefore, there is a demandfor development of excellent anticoagulants which have good doseresponsiveness, long duration, low risk of hemorrhage and little sideeffects and fast onset of sufficient effects even by oral administration(Thrombosis Research, Vol. 68, pp. 507-512, 1992).

Based on the research of anticoagulants worked through various mechanismof action, it is suggested that FXa inhibitors are promisinganticoagulants. A blood coagulation system comprises a series ofreactions that a great amount of thrombin is produced through anamplification process by multi-stage enzyme reactions to form insolublefibrin. In an endogenous system, activated factor IX activates intofactor X on a phospholipid membrane in the presence of activated factorVIII and calcium ions after multi-stage reactions subsequent toactivation of a contact factor. In an exogenous system, activated factorVII activates factor X in the presence of a tissue factor. Morespecifically, the activation of the factor X into FXa in the coagulationsystem is a crucial reaction in the formation of thrombin. The activatedfactor X (FXa) limitedly decomposes prothrombin to produce thrombin inthe both systems. Since the produced thrombin activates coagulationfactors in the upper stream, the formation of thrombin is moreamplified. As described above, since the coagulation system in the upperstream of FXa is divided into the endogenous system and the exogenoussystem, production of FXa cannot be sufficiently inhibited by inhibitingenzymes in the coagulation system in the upper stream of FXa, leading toproduction of thrombin. Since the coagulation system comprisesself-amplification reactions, inhibition of the coagulation system canbe more efficiently achieved by inhibiting FXa in the upper stream ofthrombin than the inhibition of thrombin (Thrombosis Research, Vol. 15,pp. 617-629, 1979).

An another excellent point of FXa inhibitors is a great differencebetween an effective dose in a thrombosis model and a dose elongatingbleeding time in an experimental hemorrhagic model. From thisexperimental result, FXa inhibitors are considered to be anticoagulantshaving low risk of hemorrhage.

Various compounds have been reported as FXa inhibitors. It is known thatantithrombin III and antithrombin III dependent pentasacchrides cangenerally not inhibit prothrombinase complexes which play a practicalrole in the thrombus formation in a living body (Thrombosis Research,Vol. 68, pp. 507-512, 1992; Journal of Clinical Investigation, Vol. 71,pp. 1383-1389, 1983; Mebio, Vol. 14, the August number, pp. 92-97). Inaddition, they do not exhibit effectiveness by oral administration. Tickanticoagulant peptide (TAP) (Science, Vol. 248, pp. 593-596, 1990) andantistasin (AST) (Journal of Biological Chemistry, Vol. 263, pp.10162-10167, 1988) isolated from mites or leeches, which arebloodsuckers, also inhibit Fxa and exhibit anti-thrombotic effectsagainst venous thrombosis and arterial thrombosis. However, thesecompounds are high-molecular weight peptides and unavailable in oraladministration. As described above, development of antithrombin IIIindependent low-molecular weight FXa inhibitors which directly inhibitcoagulation factors has been conducted.

It is therefore an object of the present invention to provide a novelcompound which has a potent FXa-inhibiting effect and exhibits ananti-thrombotic effect quickly, sufficiently and persistently by oraladministration.

DISCLOSURE OF THE INVENTION

The present inventors have investigated synthesis and pharmacologicaleffects of novel FXa inhibitors. As a result, diamine derivatives, saltsthereof, and solvates and N-oxides thereof, which exhibit potentFXa-inhibiting effect and anticoagulant effect, have been found. It hasalso been found that these compounds promptly, persistently and potentlyinhibit FXa and exhibit potent anticoagulant effect and anti-thromboticeffect by oral administration, and are hence useful as prophylactics andremedies for various diseases based on thromboembolism, thus leading tocompletion of the present invention.

This invention provides a compound represented by the general formula(1):

Q¹-Q²-T⁰-N(R¹)-Q³-N(R²)-T¹-Q⁴  (1)

wherein

R¹ and R², independently of each other, represent a hydrogen atom,hydroxyl group, alkyl group or alkoxy group;

Q¹ represents a saturated or unsaturated, 5- or 6-membered cyclichydrocarbon group which may be substituted, a saturated or unsaturated,5- to 7-membered heterocyclic group which may be substituted, asaturated or unsaturated, bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, bicyclic ortricyclic fused heterocyclic group which may be substituted;

Q² represents a single bond, a saturated or unsaturated, 5- or6-membered divalent cyclic hydrocarbon group which may be substituted, asaturated or unsaturated, 5- to 7-membered divalent heterocyclic groupwhich may be substituted, a saturated or unsaturated, divalent bicyclicor tricyclic fused hydrocarbon group which may be substituted, or asaturated or unsaturated, divalent bicyclic or tricyclic fusedheterocyclic group which may be substituted;

Q³ represents the following group:

in which Q⁵ means an alkylene group having 1 to 8 carbon atoms, analkenylene group having 2 to 8 carbon atoms, or a group—(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n are independently ofeach other 0 or an integer of 1-3, and A means an oxygen atom, nitrogenatom, sulfur atom, —SO—, —SO₂—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH—or —SO₂—NH—, and R³ and R⁴ are substituents on carbon atom(s), nitrogenatom(s) or a sulfur atoms of a ring comprising Q⁵ and are independentlyof each other a hydrogen atom, hydroxyl group, alkyl group, alkenylgroup, alkynyl group, halogen atom, halogenoalkyl group, cyano group,cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkylgroup, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group,acylamino group which may be substituted, alkoxyimino group,hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkylgroup, hydroxyalkyl group, carboxyl group, carboxyalkyl group,alkoxycarbonyl group, alkoxycarbonylalkyl group,alkoxycarbonylalkylamino group, carboxyalkylamino group,alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoylgroup, N-alkylcarbamoyl group which may have a substituent on the alkylgroup, N,N-dialkylcarbamoyl group which may have a substituent on thealkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group,N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group,N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group,N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberedheterocyclic carbonyl group which may be substituted, carbamoylalkylgroup, N-alkylcarbamoylalkyl group which may have a substituent on thealkyl group(s), N,N-dialkylcarbamoylalkyl group which may have asubstituent on the alkyl group(s), carbamoyloxyalkyl group,N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3-to 6-membered heterocyclic carbonylalkyl group which may be substituted,3- to 6-membered heterocyclic carbonyloxyalkyl group which may besubstituted, aryl group, aralkyl group, heteroaryl group,heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylaminogroup, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group,alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group,alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkylgroup, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxygroup, acyloxy group, acyloxyalkyl group, arylsulfonyl group,alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacylgroup, alkoxyacyl group, halogenoacyl group, carboxyacyl group,aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group,hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-memberedheterocyclic sulfonyl group which may be substituted, N-alkylaminoacylgroup, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group whichmay have a substituent on the alkyl group(s),N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent onthe alkyl group(s) or alkylsulfonylacyl group, or R³ and R⁴, togetherwith each other, denote an alkylene group having 1 to 5 carbon atoms,alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having1 to 5 carbon atoms or carbonyldioxy group;

Q⁴ represents an aryl group which may be substituted, an arylalkenylgroup which may be substituted, an arylalkynyl group which may besubstituted, a heteroaryl group which may be substituted, aheteroarylalkenyl group which may be substituted, a saturated orunsaturated, bicyclic or tricyclic fused hydrocarbon group which may besubstituted, or a saturated or unsaturated, bicyclic or tricyclic fusedheterocyclic group which may be substituted;

T⁰ represents a carbonyl or thiocarbonyl group; and

T¹ represents a carbonyl group, sulfonyl group, group—C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group—C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)—, in which R′ means ahydrogen atom, hydroxyl group, alkyl group or alkoxy group, group—C(═O)-A¹-N(R″)—, in which A¹ means an alkylene group having 1 to 5carbon atoms, which may be substituted, and R″ means a hydrogen atom,hydroxyl group, alkyl group or alkoxy group, group —C(═O)—NH—, group—C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A²-C(═O)—, in which A²means a single bond or alkylene group having 1 to 5 carbon atoms, group—C(═O)-A³-C(═O)—NH—, in which A³ means an alkylene group having 1 to 5carbon atoms, group —C(═O)—C(═NOR^(a))—N(R^(b))—, group—C(═S)—C(═NOR^(a))—N(R^(b))—, in which R^(a) means a hydrogen atom,alkyl group or alkanoyl group, and R^(b) means a hydrogen atom, hydroxylgroup, alkyl group or alkoxy group, group —C(═O)—N═N—, group—C(═S)—N═N—, or thiocarbonyl group;

a salt thereof, a solvate thereof, or an N-oxide thereof.

This invention also provides a medicine, an activated blood coagulationfactor X inhibitor, an anticoagulant, an agent for preventing and/ortreating thrombosis or embolism and an agent for preventing and/ortreating cerebral infarction, cerebral embolism, myocardial infarction,angina pectoris, pulmonary infarction, pulmonary embolism, Buerger'sdisease, deep venous thrombosis, disseminated intravascular coagulationsyndrome, thrombus formation after valve or joint replacement, thrombusformation and reocclusion after angioplasty, systemic inflammatoryresponse syndrome (SIRS), multiple organ dysfunction syndrome (MODS),thrombus formation during extracorporeal circulation, or blood clottingupon blood gathering, which each comprises the compound represented bythe general formula (1), the salt thereof, the solvate thereof, orN-oxide thereof.

This invention further provides an intermediate useful for preparing thecompound represented by the general formula (1).

This invention still further provides use of the compound represented bythe general formula (1), the salt thereof, the solvate thereof, orN-oxide thereof for preparation of a medicine.

This invention yet still further provides a method for treatingthrombosis or embolism, which comprises administering an effectiveamount of the compound represented by the general formula (1), the saltthereof, the solvate thereof, or N-oxide thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

Substituents in the diamine derivatives according to the presentinvention represented by the general formula (1) will hereinafter bedescribed.

<On Group Q⁴>

The group Q⁴ means an aryl group which may be substituted, anarylalkenyl group which may be substituted, an arylalkynyl group whichmay be substituted, a heteroaryl group which may be substituted, aheteroarylalkenyl group which may be substituted, a saturated orunsaturated, bicyclic or tricyclic fused hydrocarbon group which may besubstituted, or a saturated or unsaturated, bicyclic or tricyclic fusedheterocyclic group which may be substituted.

In the group Q⁴, the aryl group may include aryl groups having 6 to 14carbon atoms, for example, phenyl, naphthyl, anthryl and phenanthrylgroups. The arylalkenyl group means a group formed by an aryl grouphaving 6 to 14 carbon atoms and an alkenylene group having 2 to 6 carbonatoms, and examples thereof may include a styryl group. The arylalkynylgroup means a group formed by an aryl group having 6 to 14 carbon atomsand an alkynylene group having 2 to 6 carbon atoms, and examples thereofmay include a phenylethynyl group.

The heteroaryl group means a monovalent aromatic group having at leastone hetero atom selected from oxygen, sulfur and nitrogen atoms, andexamples thereof may include 5- or 6-membered heteroaryl groups, forexample, pyridyl, pyridazinyl, furyl, thienyl, pyrrolyl, thiazolyl,oxazolyl, pyrimidinyl and tetrazolyl groups. The heteroarylalkenyl groupmeans a group formed by the above-described heteroaryl group and analkenylene group having 2 to 6 carbon atoms, and examples thereof mayinclude thienylethenyl and pyridylethenyl groups.

The saturated or unsaturated, bicyclic or tricyclic fused hydrocarbongroup means a monovalent group derived from a saturated or unsaturated,bicyclic or tricyclic fused hydrocarbon. The saturated or unsaturated,bicyclic or tricyclic fused hydrocarbon denotes a bicyclic or tricyclicfused hydrocarbon formed by fusing 2 or 3 saturated or unsaturated, 5-or 6-membered cyclic hydrocarbons which are the same or different fromeach other. In this case, examples of the saturated or unsaturated, 5-or 6-membered cyclic hydrocarbons may include cyclopentane,cyclopentene, cyclohexane, cyclohexene, cyclohexadiene and benzene.Specific examples of the saturated or unsaturated, bicyclic or tricyclicfused hydrocarbon group may include indenyl, indanyl, tetrahydronaphthyland naphthyl groups. Incidentally, the position of the saturated orunsaturated, bicyclic or tricyclic fused hydrocarbon group bonded to T¹in the general formula (1) is not particularly limited.

The saturated or unsaturated, bicyclic or tricyclic fused heterocyclicgroup means a monovalent group derived from a saturated or unsaturated,bicyclic or tricyclic fused heterocyclic ring. The saturated orunsaturated, bicyclic or tricyclic fused heterocyclic ring denotes thefollowing heterocyclic ring {circle around (1)}, {circle around (2)} or{circle around (3)}:

{circle around (1)}: a bicyclic or tricyclic fused heterocyclic ringformed by fusing 2 or 3 saturated or unsaturated, 5- to 7-memberedheterocyclic rings which are the same or different from each other;

{circle around (2)}: a bicyclic or tricyclic fused heterocyclic ringformed by fusing a saturated or unsaturated, 5- to 7-memberedheterocyclic ring with 1 or 2 saturated or unsaturated, 5- or 6-memberedcyclic hydrocarbons; or

{circle around (3)}: a tricyclic fused heterocyclic ring formed byfusing 2 saturated or unsaturated, 5- to 7-membered heterocyclic ringswith a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon.

The position of the saturated or unsaturated, bicyclic or tricyclicfused heterocyclic group bonded to T¹ in the general formula (1) is notparticularly limited.

The saturated or unsaturated, 5- to 7-membered heterocyclic ring denotesa heterocyclic ring having at least one hetero atom selected fromoxygen, sulfur and nitrogen atoms, and specific examples thereof mayinclude furan, pyrrole, thiophene, pyrazole, imidazole, oxazole,oxazolidine, thiazole, thiadiazole, furazane, pyrane, pyridine,pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine,oxadiazine, morpholine, thiazine, thiadiazine, thiomorpholine,tetrazole, triazole, triazine, thiadiazine, oxadiazine, azepine,diazepine, triazepine, thiazepine and oxazepine. The saturated orunsaturated, 5- or 6-membered cyclic hydrocarbon denotes the samesaturated or unsaturated, 5- or 6-membered cyclic hydrocarbon as shownin the description of the saturated or unsaturated, bicyclic ortricyclic fused hydrocarbon group. Specific examples of the saturated orunsaturated, bicyclic or tricyclic fused heterocyclic group may includebenzofuryl, isobenzofuryl, benzothienyl, indolyl, indolinyl, isoindolyl,isoindolinyl, indazolyl, quinolyl, dihydroquinolyl, 4-oxodihydroquinolyl(dihydroquinolin-4-on), tetrahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, chromenyl, chromanyl, isochromanyl,4H-4-oxobenzopyranyl, 3,4-dihydro-4H-4-oxobenzopyranyl, 4H-quinolizinyl,quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl,tetrahydroquinoxalinyl, cinnolinyl, tetrahydrocinnolinyl, indolizinyl,tetrahydroindolizinyl, benzothiazolyl, tetrahydrobenzothiazolyl,benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, benzimidazolyl,naphthyridinyl, tetrahydronaphthyridinyl, thienopyridyl,tetrahydrothienopyridyl, thiazolopyridyl, tetrahydrothiazolopyridyl,thiazolopyridazinyl, tetrahydrothiazolopyridazinyl, pyrrolopyridyl,dihydropyrrolopyridyl, tetrahydropyrrolopyridyl, pyrrolopyrimidinyl,dihydropyrrolopyrimidinyl, pyridoquinazolinyl,dihydropyridoquinazolinyl, pyridopyrimidinyl,tetrahydropyridopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl,furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl,tetrahydrooxazolopyridyl, oxazolopyridazinyl,tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl,pyrrolooxazolyl, dihydropyrrolooxazolyl, thienopyrrolyl,thiazolopyrimidinyl, 4-oxotetrahydrocinnolinyl, 1,2,4-benzothiadiazinyl,1,1-dioxy-2H-1,2,4-benzothiadiazinyl, 1,2,4-benzoxadiazinyl,cyclopentapyranyl, thienofuranyl, furopyranyl, pyridoxazinyl,pyrazoloxazolyl, imidazothiazolyl, imidazopyridyl,tetrahydroimidazopyridyl, pyrazinopyridazinyl, benzoisoquinolyl,furocinnolyl, pyrazolothiazolopyridazinyl,tetrahydropyrazolothiazolopyridazinyl,hexahydrothiazolopyridazinopyridazinyl, imidazotriazinyl,oxazolopyridyl, benzoxepinyl, benzoazepinyl, tetrahydrobenzoazepinyl,benzodiazepinyl, benzotriazepinyl, thienoazepinyl,tetrahydrothienoazepinyl, thienodiazepinyl, thienotriazepinyl,thiazoloazepinyl, tetrahydrothiazoloazepinyl,4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups.

No particular limitation is imposed on the fusing form of the fusedheterocyclic group. For example, the naphthyridinyl group may be any of1,5-, 1,6-, 1,7-, 1,8-, 2,6- and 2,7-naphthyridinyl groups, thethienopyridyl group may be any of thieno[2,3-b]pyridyl,thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,2-c]pyridyl,thieno[3,4-b]pyridyl and thieno[3,4-c]pyridyl groups, the thienopyrrolylgroup may be any of thieno[2,3-b]pyrrolyl and thieno[2,3-b]pyrrolylgroups, the thiazolopyridyl group may be any of thiazolo[4,5-b]pyridyl,thiazolo[4,5-c]pyridyl, thiazolo[5,4-b]pyridyl, thiazolo[5,4-c]pyridyl,thiazolo[3,4-a]pyridyl and thiazolo[3,2-a]pyridyl groups, thethiazolopyridazinyl group may be any of thiazolo-[4,5-c]pyridazinyl,thiazolo[4,5-d]pyridazinyl, thiazolo[5,4-c]pyridazinyl andthiazolo[3,2-b]pyridazinyl groups, the pyrrolopyridyl may be any ofpyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-b]pyridyl,pyrrolo[3,2-c]pyridyl, pyrrolo[3,4-b]pyridyl and pyrrolo[3,4-c]pyridylgroup, the pyridopyrimidinyl group may be any ofpyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[1,2-c]pyrimidinyl and pyrido[1,2-a]pyrimidinyl groups, thepyranothiazolyl group may be any of pyrano[2,3-d]thiazolyl,pyrano[4,3-d]thiazolyl, pyrano[3,4-d]thiazolyl andpyrano[3,2-d]thiazolyl groups, the furopyridyl group may be any offuro[2,3-b]pyridyl, furo[2,3-c]pyridyl, furo[3,2-b]pyridyl,furo[3,2-c]pyridyl, furo[3,4-b]pyridyl and furo[3,4-c]pyridyl groups,the oxazolopyridyl group may be any of oxazolo[4,5-b]pyridyl,oxazolo[4,5-c]pyridyl, oxazolo[5,4-b]pyridyl, oxazolo[5,4-c]pyridyl,oxazolo[3,4-a]pyridyl and oxazolo[3,2-a]pyridyl groups, theoxazolopyridazinyl group may be any of oxazolo[4,5-c]pyridazinyl,oxazolo[4,5-d]pyridazinyl, oxazolo[5,4-c]pyridazinyl andoxazolo[3,4-b]pyridazinyl groups, the pyrrolothiazolyl group may be anyof pyrrolo[2,1-b]thiazolyl, pyrrolo[1,2-c]thiazolyl,pyrrolo[2,3-d]thiazolyl, pyrrolo[3,2-d]thiazolyl andpyrrolo[3,4-d]thiazolyl groups, the pyrrolooxazolyl group may be any ofpyrrolo[2,1-b]oxazolyl, pyrrolo[1,2-c]oxazolyl, pyrrolo[2,3-d]oxazolyl,pyrrolo[3,2-d]oxazolyl and pyrrolo[3,4-d]oxazolyl groups, thebenzoazepinyl group may be any of 1H-1-benzoazepinyl, 1H-2-benzoazepinyland 1H-3-benzoazepinyl groups, or may be a dihydro-oxo derivative typebenzoazepinyl group such as 4,5-dihydro-1-oxo-1H-2-benzoazepinyl group,the benzodiazepinyl group may be any of 1H-1,3-benzodiazepinyl,1H-1,4-benzodiazepinyl and 1H-1,5-benzodiazepinyl groups, or may be adihydro-oxo derivative type benzodiazepinyl group such as4,5-dihydro-4-oxo-1H-1,3-benzodiazepinyl group, the benzotriazepinylgroup may be any of 1H-1,3,4-benzotriazepinyl and1H-1,3,5-benzotriazepinyl groups, or may be a dihydro-oxo derivativetype benzotriazepinyl group such as4,5-dihydro-5-oxo-1H-1,3,4-benzotriazepinyl group, and thethienoazepinyl group may be any of thieno[2,3-b]azepinyl,thieno[2,3-c]azepinyl, thieno-[2,3-d]azepinyl, thieno[3,2-c]azepinyl andthieno[3,2-b]azepinyl groups, or may be a dihydro-oxo derivative typethienoazepinyl group such as5,6,7,8-tetrahydro-4-oxo-4H-thieno[3,2-c]azepinyl group.Thienodiazepinyl and thienotriazepinyl groups may also be any fusingforms, or may be those of the dihydro-oxo derivative type. Thebenzothiazepinyl group may be any of 1H-1-benzothiazepinyl,1H-2-benzothiazepinyl and 1H-3-benzothiazepinyl groups, or may be adihydro-oxo derivative type benzothiazepinyl group such as4,5-dihydro-1-oxo-1H-2-benzothiazepinyl group, and the benzoxazepinylgroup may be any of 1H-1-benzoxazepinyl, 1H-2-benzoxazepinyl and1H-3-benzoxazepinyl groups, or may be a dihydro-oxo derivative typebenzoxazepinyl group such as 4,5-dihydro-1-oxo-1H-2-benzoxazepinylgroup. Other fusing forms than these may be allowed.

The above-described aryl groups, heteroaryl groups, arylalkenyl group,heteroarylalkenyl groups, saturated or unsaturated, bicyclic ortricyclic fused hydrocarbon groups and saturated or unsaturated,bicyclic or tricyclic fused heterocyclic groups may each have 1 to 3substituents. Examples of the substituents may include a hydroxyl group,halogen atoms such as fluorine atom, chlorine atom, bromine atom andiodine atom, halogenoalkyl groups having 1 to 6 carbon atoms substitutedby 1 to 3 halogen atoms, an amino group, a cyano group, aminoalkylgroups, a nitro group, hydroxyalkyl groups (for example, hydroxymethylgroup, 2-hydroxyethyl group, etc.), alkoxyalkyl groups (for example,methoxymethyl group, 2-methoxyethyl group, etc.), a carboxyl group,carboxyalkyl groups (for example, carboxymethyl group, 2-carboxyethylgroup, etc.), alkoxycarbonylalkyl groups (for example,methoxycarbonylmethyl group, ethoxycarbonylmethyl group, etc.), acylgroups (for example, alkanoyl groups such as formyl group, acetyl groupand propionyl group), an amidino group, a hydroxyamidino group, linear,branched or cyclic alkyl groups having 1 to 6 carbon atoms (for example,methyl group, ethyl group, etc.), linear, branched or cyclic alkoxygroups having 1 to 6 carbon atom (for example, methoxy group, ethoxygroup, etc.), amidino groups substituted by an alkoxycarbonyl grouphaving 2 to 7 carbon atoms (for example, methoxycarbonylamidino group,ethoxycarbonylamidino group, etc.), linear, branched or cyclic alkenylgroups having 2 to 6 carbon atoms (for example, vinyl group, allylgroup, etc.), linear or branched alkynyl groups having 2 to 6 carbonatoms (for example, ethynyl group, propynyl group, etc.), linear,branched or cyclic alkoxycarbonyl groups having 2 to 6 carbon atoms (forexample, methoxycarbonyl group, ethoxycarbonyl group, etc.), a carbamoylgroup, mono- or di-alkylcarbamoyl groups substituted by a linear,branched or cyclic alkyl groups having 1 to 6 carbon atoms on thenitrogen atom(s), mono- or di-alkylamino groups substituted by 1 or 2linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms (forexample, ethylamino, dimethylamino and methylethylamino groups), and 5-or 6-membered nitrogen-containing heterocyclic groups (for example,pyrrolidino group, piperidino group, piperazino group, morpholino group,etc.).

As the group Q⁴, are preferred the following 12 groups (a) to (1) amongthe above-described groups. Namely,

wherein R⁵ and R⁶, independently of each other, represent a hydrogenatom, cyano group, halogen atom, alkyl group, hydroxyalkyl group, alkoxygroup, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acylgroup, alkoxycarbonyl group, alkoxycarbonylalkyl group, or phenyl groupwhich may be substituted by a cyano group, hydroxyl group, halogen atom,alkyl group or alkoxy group, and R⁷ and R⁸, independently of each other,represent a hydrogen atom, hydroxyl group, nitro group, amino group,cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group,halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkylgroup, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group,N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonylgroup, amidino group or alkoxycarbonylalkyl group;

wherein R⁹ and R¹⁰, independently of each other, represent a hydrogenatom, hydroxyl group, nitro group, amino group, cyano group, halogenatom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group,hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group,carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group;

wherein R¹¹, R¹² and R¹³, independently of one another, represent ahydrogen atom, hydroxyl group, nitro group, amino group, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkylgroup, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxylgroup, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoylgroup, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino groupor alkoxycarbonylalkyl group;

wherein X¹ represents CH₂, CH, NH, NOH, N, O or S, and R¹⁴, R¹⁵ and R¹⁶,independently of one another, represent a hydrogen atom, hydroxyl group,nitro group, amino group, cyano group, halogen atom, alkyl group,alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group,alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group,acyl group, carbamoyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group;

wherein X² represents NH, N, O or S, X³ represents N, C or CH, X⁴represents N, C or CH, and R¹⁷ and R¹⁸, independently of each other,represent a hydrogen atom, hydroxyl group, nitro group, amino group,cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group,halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkylgroup, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group,N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonylgroup, amidino group or alkoxycarbonylalkyl group, excluding the caseswhere X³ and X⁴ are combinations of C and CH, and are both C or CH;

wherein N indicates that 1 or 2 carbon atoms of the ring substituted byR¹⁹ have been substituted by a nitrogen atom, and R¹⁹, R²⁰ and R²¹,independently of one another, represent a hydrogen atom, hydroxyl group,nitro group, amino group, cyano group, halogen atom, alkyl group,alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group,alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group,acyl group, carbamoyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group;

wherein X⁵ represents CH₂, CH, N or NH, Z¹ represents N, NH or O, Z²represents CH₂, CH, C or N, Z³ represents CH₂, CH, S, SO₂ or C═O, X⁵-Z²indicates that X⁵ and Z² are bonded to each other by a single bond ordouble bond, R²² and R²³, independently of each other, represent ahydrogen atom, hydroxyl group, nitro group, amino group, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkylgroup, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxylgroup, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoylgroup, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino groupor alkoxycarbonylalkyl group, and R²⁴ represents a hydrogen atom oralkyl group;

wherein X⁶ represents O or S, and R²⁵ and R²⁶, independently of eachother, represent a hydrogen atom, hydroxyl group, nitro group, aminogroup, cyano group, halogen atom, alkyl group, alkenyl group, alkynylgroup, halogenoalkyl group, hydroxyalkyl group, alkoxy group,alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group,carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group,alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group;

wherein R²⁷ and R²⁸, independently of each other, represent a hydrogenatom, hydroxyl group, nitro group, amino group, cyano group, halogenatom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group,hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group,carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group;

wherein E¹ and E², independently of each other, represent N or CH, andR²⁹ and R³⁰, independently of each other, represent a hydrogen atom,hydroxyl group, nitro group, amino group, cyano group, halogen atom,alkyl group, alkenyl group, alkynyl group, halogenoalkyl group,hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group,carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group;

wherein Y¹ represents CH or N, Y² represents —N(R³³)—, in which R³³means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S,and R³¹ and R³², independently of each other, represent a hydrogen atom,hydroxyl group, nitro group, amino group, cyano group, halogen atom,alkyl group, alkenyl group, alkynyl group, halogenoalkyl group,hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group,carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group; and

wherein numerals 1 to 8 indicate positions, each N indicates that anyone of carbon atoms of positions 1 to 4 and any one of carbon atoms ofpositions 5 to 8 has been substituted by a nitrogen atom, and R³⁴, R³⁵and R³⁶, independently of one another, represent a hydrogen atom,hydroxyl group, nitro group, amino group, cyano group, halogen atom,alkyl group, alkenyl group, alkynyl group, halogenoalkyl group,hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group,carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group.

These groups will hereinafter be described.

In the description of R⁵ to R³⁶, the halogen atom is a fluorine,chlorine, bromine or iodine atom, the alkyl group is a linear, branchedor cyclic alkyl group having 1 to 6 carbon atoms, the alkenyl group is alinear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms,the alkynyl group is a linear or branched alkynyl groups having 2 to 6carbon atoms, the hydroxyalkyl group means the above-described C₁-C₆alkyl group substituted by a hydroxyl group, the alkoxy group is alinear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, thealkoxyalkyl group means the above-described C₁-C₆ alkyl groupsubstituted by the above-described C₁-C₆ alkoxy group, the carboxyalkylgroup means the above-described C₁-C₆ alkyl group substituted by acarboxyl group, the acyl group is an alkanoyl group (including formyl)having 1 to 6 carbon atom, an aroyl group such as a benzoyl or naphthoylgroup, or an arylalkanoyl group with the above-described C₆-C₁₄ arylgroup substituted on the above-described C₁-C₆ alkanoyl group, theN-alkylcarbamoyl group means a carbamoyl group with the above-describedC₁-C₆ alkyl group substituted on the nitrogen atom, theN,N-dialkylcarbamoyl group means a carbamoyl group with two of theabove-described C₁-C₆ alkyl groups substituted on the nitrogen atom, thealkoxycarbonyl group is a group composed of the above-described C₁-C₆alkoxy group and a carbonyl group, the alkoxycarbonylalkyl group meansthe above-described C₁-C₆ alkyl group substituted by the above-describedC₁-C₆ alkoxycarbonyl group, and the halogenoalkyl group means theabove-described C₁-C₆ alkyl group substituted by 1 to 3 halogen atoms.Incidentally, in the above description, no particular limitation isimposed on the substituting position.

In the following group:

wherein R⁵, R⁶, R⁷ and R⁸ have the same meanings as defined above, andnumerals 1 to 6 indicate positions, R⁵ and R⁶, independently of eachother, are preferably a hydrogen atom, cyano group, halogen atom, alkylgroup, alkenyl group, alkynyl group or halogenoalkyl group. R⁵ and R⁶are more preferably hydrogen atoms or alkyl groups. In the case of thealkyl group, a methyl group is preferred. It is preferable that one ofR⁷ and R⁸ is a hydrogen atom, and the other is a hydrogen atom, cyanogroup, halogen atom, alkyl group, alkenyl group, alkynyl group orhalogenoalkyl group. Among others, it is particularly preferred that theother group be a hydrogen atom, halogen atom, alkyl group or alkynylgroup. In this case, the halogen atom is preferably a fluorine, chlorineor bromine atom. As the alkyl group, is preferred a methyl group. As thealkynyl group, is particularly preferred an ethynyl group. As specificpreferable examples of the group represented by the above formula, maybe mentioned chlorostyryl, fluorostyryl, bromostyryl and ethynylstyrylgroups. The position substituted by the halogen atom, alkyl group oralkynyl group is particularly preferably a 4-position in the aboveformula though it should not be particularly limited. As specificpreferable examples thereof, may be mentioned 4-chlorostyryl,4-fluorostyryl, 4-bromostyryl and 4-ethynylstyryl groups.

In the following group:

wherein R⁹ and R¹⁰ have the same meanings as defined above, and numerals1 to 6 indicate positions, R⁹ and R¹⁰, independently of each other, arepreferably a hydrogen atom, halogen atom, alkyl group or alkynyl group.It is further preferable that R⁹ is a hydrogen atom, and R¹⁰ is ahydrogen atom, halogen atom, alkyl group or alkynyl group. In this case,the halogen atom is preferably a fluorine, chlorine or bromine atom. Asthe alkyl group, is preferred a methyl group. As the alkynyl group, isparticularly preferred an ethynyl group. As specific preferable examplesof the group represented by the above formula, may be mentionedchlorophenylethynyl, fluorophenylethynyl, bromophenylethynyl andethynylphenylethynyl groups. The position substituted by the halogenatom, alkyl group or alkynyl group is particularly preferably a4-position in the above formula though it should not be particularlylimited. As specific preferable examples thereof, may be mentioned4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl and4-ethynylphenylethynyl groups.

In the following group:

wherein R¹¹, R¹² and R¹³ have the same meanings as defined above, andnumerals 1 to 8 indicate positions, R¹¹, R¹² and R¹³ are, independentlyof one another, preferably a hydrogen atom, cyano group, halogen atom,alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. R¹¹ ispreferably a hydrogen atom, alkyl group, halogen atom or hydroxyl group,with a hydrogen atom particularly preferred. It is preferable that oneof R¹² and R¹³ is a hydrogen atom, and the other is a hydrogen atom,cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group orhalogenoalkyl group. Among others, it is particularly preferred that theother group be a hydrogen atom, halogen atom, alkyl group or alkynylgroup. In this case, the halogen atom is preferably a fluorine, chlorineor bromine atom. As the alkyl group, is preferred a methyl group. As thealkynyl group, is preferred an ethynyl group. In the naphthyl group, a2-naphthyl group is preferred to a 1-naphthyl group. In the case of the2-naphthyl group, a position substituted by a halogen atom, alkyl groupor alkynyl group is preferably a 6- or 7-position in the above formulathough it should not be particularly limited, with a 6-position beingmost preferred. These naphthyl groups are preferably substituted by achlorine, fluorine or bromine atom, an alkynyl group, or the like, witha group having a substituents such as a chlorine, fluorine or bromineatom, an alkynyl group, or the like at the above-described position inthe above formula being particularly preferred. As specific preferableexamples thereof, may be mentioned 6-chloro-2-naphthyl,6-fluoro-2-naphthyl, 6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl,7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo-2-naphthyl and7-ethynyl-2-naphthyl groups.

In the following group:

wherein X¹, R¹⁴, R¹⁵ and R¹⁶ have the same meanings as defined above,and numerals 4 to 7 indicate positions, X¹ is preferably NH, NOH, N, Oor S, with NH, O or S being particularly preferred. R¹⁴ is preferably ahydrogen atom, halogen atom, acyl group, N-alkylcarbamoyl group,N,N-dialkylcarbamoyl group or alkyl group, and R¹⁵ and R¹⁶ are,independently of each other, preferably a hydrogen atom, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkylgroup. It is preferable that one of R¹⁵ and R¹⁶ is a hydrogen or ahalogen atom, preferably fluorine atom or chlorine atom, and the otheris a hydrogen atom, cyano group, halogen atom, alkyl group, alkenylgroup, alkynyl group or halogenoalkyl group. Among others, it isparticularly preferred that the other group be a hydrogen atom, halogenatom, alkyl group or alkynyl group. In this case, the halogen atom ispreferably a fluorine, chlorine or bromine atom. As the alkyl group, ispreferred a methyl group. As the alkynyl group, is preferred an ethynylgroup. The position substituted by the halogen atom, alkyl group oralkynyl group is preferably a 4-, 5- or 6-position in the above formulathough it should be not particularly limited. As specific preferableexamples of the group represented by the above formula, may be mentioned5-chloroindolyl, 5-fluoroindolyl, 5-bromoindolyl, 5-ethynylindolyl,5-methylindolyl, 5-chloro-4-fluoroindolyl, 5-chloro-3-fluoroindolyl,5-fluoro-3-chloroindolyl, 5-ethynyl-3-fluoroindolyl,5-chloro-3-(N,N-dimethylcarbamoyl)indolyl,5-fluoro-3-(N,N-dimethylcarbamoyl)indolyl, 5-chloro-3-formylindolyl,5-fluoro-3-formylindolyl, 6-chloroindolyl, 6-fluoroindolyl,6-bromoindolyl, 6-ethynylindolyl, 6-methylindolyl, 5-chlorobenzothienyl,5-fluorobenzothienyl, 5-bromobenzothienyl, 5-ethynylbenzothienyl,5-methylbenzothienyl, 5-chloro-4-fluorobenzothienyl,6-chlorobenzothienyl, 6-fluorobenzothienyl, 6-bromobenzothienyl,6-ethynylbenzothienyl, 6-methylbenzothienyl, 5-chlorobenzofuryl,5-fluorobenzofuryl, 5-bromobenzofuryl, 5-ethynylbenzofuryl,5-methylbenzofuryl, 5-chloro-4-fluorobenzofuryl, 6-chlorobenzofuryl,6-fluorobenzofuryl, 6-bromobenzofuryl, 6-ethynylbenzofuryl and6-methylbenzofuryl groups. The position of the above-describedsubstituent group bonded to T¹ is not particularly limited, but ispreferably a 2-position or 3-position in the formula (d). Specifically,more preferred are 5-chloroindol-2-yl, 5-fluoroindol-2-yl,5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl,5-chloro-4-fluoroindol-2-yl, 5-chloro-3-fluoroindol-2-yl,3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl,3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl,5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl,5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl,5-ethynyl-3-formylindol-2-yl,5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl,5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl,5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl,5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl, 6-chloroindol-2-yl,6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl,6-methylindol-2-yl, 5-chloroindol-3-yl, 5-fluoroindol-3-yl,5-bromoindol-3-yl, 5-ethynylindol-3-yl, 5-methylindol-3-yl,5-chloro-4-fluoroindol-3-yl, 6-chloroindol-3-yl, 6-fluoroindol-3-yl,6-bromoindol-3-yl, 6-ethynylindol-3-yl, 6-methylindol-3-yl,5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl,5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl,5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl,6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl,6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl,6-methylbenzothiophen-2-yl, 5-chlorobenzothiophen-3-yl,5-fluorobenzothiophen-3-yl, 5-bromobenzothiophen-3-yl,5-ethynylbenzothiophen-3-yl, 5-methylbenzothiophen-3-yl,5-chloro-4-fluorobenzothiophen-3-yl, 6-chlorobenzothiophen-3-yl,6-fluorobenzothiophen-3-yl, 6-bromobenzothiophen-3-yl,6-ethynylbenzothiophen-3-yl, 6-methylbenzothiophen-3-yl,5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl,5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl,5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl,6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl,6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl,6-methylbenzofuran-2-yl, 5-chlorobenzofuran-3-yl,5-fluorobenzofuran-3-yl, 5-bromobenzofuran-3-yl,5-ethynylbenzofuran-3-yl, 5-methylbenzofuran-3-yl,5-chloro-4-fluorobenzofuran-3-yl, 6-chlorobenzofuran-3-yl,6-fluorobenzofuran-3-yl, 6-bromobenzofuran-3-yl,6-ethynylbenzofuran-3-yl and 6-methylbenzofuran-3-yl groups, with5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl,5-ethynylindol-2-yl, 5-methylndol-2-yl, 5-chloro-4-fluoroindol-2-yl,6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl,6-ethynylindol-2-yl, 6-methylndol-2-yl, 5-chloro-3-fluoroindol-2-yl,3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl,3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl,5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl,5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl,5-ethynyl-3-formylindol-2-yl,5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl,5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl,5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl,5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl,5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl,5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl,5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl,6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl,6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl,6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl,5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl,5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl,5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl,6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl,6-ethynylbenzofuran-2-yl and 6-methylbenzofuran-2-yl groups beingparticularly preferred.

In the following group:

wherein X², X³, X⁴, R¹⁷ and R¹⁸ have the same meanings as defined above,and numerals 4 to 7 indicate positions, X² is preferably NH, O or S, anyone of X³ and X⁴ is preferably CH or C, particularly preferably C. R¹⁷and R¹⁸ are, independently of each other, preferably a hydrogen atom,cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group orhalogenoalkyl group. It is preferable that one of R¹⁷ and R¹⁸ is ahydrogen atom, and the other is a hydrogen atom, cyano group, halogenatom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group.Among others, it is particularly preferred that the other group be ahydrogen atom, halogen atom, alkyl group or alkynyl group. In this case,the halogen atom is preferably a fluorine, chlorine or bromine atom. Asthe alkyl group, is preferred a methyl group. As the alkynyl group, ispreferred an ethynyl group. The position substituted by the halogenatom, alkyl group or alkynyl group is preferably a 5- or 6-position inthe above formula though it should not be particularly limited. Asspecific preferable examples of the group represented by the aboveformula, may be mentioned 5-chloroindazolyl, 5-fluoroindazolyl,5-bromoindazolyl, 5-ethynylindazolyl, 6-chloroindazolyl,6-fluoroindazolyl, 6-bromoindazolyl, 6-ethynylindazolyl,5-chlorobenzimidazolyl, 5-fluorobenzimidazolyl, 5-bromobenzimidazolyl,5-ethynylbenzimidazolyl, 6-chlorobenzimidazolyl, 6-fluorobenzimidazolyl,6-bromobenzimidazolyl, 6-ethynylbenzimidazolyl, 5-chlorobenzothiazolyl,5-fluorobenzothiazolyl, 5-bromobenzothiazolyl, 5-ethynylbenzothiazolyl,6-chlorobenzothiazolyl, 6-fluorobenzothiazolyl, 6-bromobenzothiazolyl,6-ethynylbenzothiazolyl, 5-chlorobenzoxazolyl, 5-fluorobenzoxazolyl,5-bromobenzoxazolyl, 5-ethynylbenzoxazolyl, 6-chlorobenzoxazolyl,6-fluorobenzoxazolyl, 6-bromobenzoxazolyl, 6-ethynylbenzoxazolyl,5-chlorobenzoisothiazolyl, 5-fluorobenzoisothiazolyl,5-bromobenzoisothiazolyl, 5-ethynylbenzoisothiazolyl,6-chlorobenzoisothiazolyl, 6-fluorobenzoisothiazolyl,6-bromobenzoisothiazolyl, 6-ethynylbenzoisothiazolyl,5-chlorobenzoisoxazolyl, 5-fluorobenzoisoxazolyl,5-bromobenzoisoxazolyl, 5-ethynylbenzoisoxazolyl,6-chlorobenzoisoxazolyl, 6-fluorobenzoisoxazolyl, 6-bromobenzoisoxazolyland 6-ethynylbenzoisoxazolyl groups. The position of the above-describedsubstituent group bonded to T¹ is not particularly limited. Morepreferred are 5-chloroindazol-3-yl, 5-fluoroindazol-3-yl,5-bromoindazol-3-yl, 5-ethynylindazol-3-yl, 6-chloroindazol-3-yl,6-fluoroindazol-3-yl, 6-bromoindazol-3-yl, 6-ethynylindazol-3-yl,5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl,5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl,6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl,6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl,5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl,5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl,6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl,6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl,5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl,5-bromobenzoxazol-2-yl, 5-ethynylbenzoxazol-2-yl,6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl,6-bromobenzoxazol-2-yl, 6-ethynylbenzoxazol-2-yl,5-chlorobenzoisothiazol-3-yl, 5-fluorobenzoisothiazol-3-yl,5-bromobenzoisothiazol-3-yl, 5-ethynylbenzoisothiazol-3-yl,6-chlorobenzoisothiazol-3-yl, 6-fluorobenzoisothiazol-3-yl,6-bromobenzoisothiazol-3-yl, 6-ethynylbenzoisothiazol-3-yl,5-chlorobenzoisoxazol-3-yl, 5-fluorobenzoisoxazol-3-yl,5-bromobenzoisoxazol-3-yl, 5-ethynylbenzoisoxazol-3-yl,6-chlorobenzoisoxazol-3-yl, 6-fluorobenzoisoxazol-3-yl,6-bromobenzoisoxazol-3-yl and 6-ethynylbenzoisoxazol-3-yl groups, with5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl,5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl,6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl,6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl,5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazole-2-yl,5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazole-2-yl,6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazole-2-yl,6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazole-2-yl,5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl,5-bromobenzoxazol-2-yl, 5-ethynylbenzoxazol-2-yl,6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl, 6-bromobenzoxazol-2-yland 6-ethynylbenzoxazol-2-yl groups being particularly preferred. Amongthese, 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl,5-bromobenzimidazol-2-yl and 5-ethynylbenzimidazol-2-yl are furtherpreferred.

In the following group:

wherein N indicates that 1 or 2 carbon atoms of the ring substituted byR¹⁹ have been substituted by a nitrogen atom, R¹⁹, R²⁰ and R²¹ have thesame meanings as defined above, and numerals 5 to 8 indicate positions,R¹⁹, R²⁰ and R²¹ are, independently of each other, preferably a hydrogenatom, cyano group, halogen atom, alkyl group, alkenyl group, alkynylgroup or halogenoalkyl group. R¹⁹ is particularly preferably a hydrogenatom. It is preferable that one of R²⁰ and R²¹ is a hydrogen atom, andthe other is a hydrogen atom, cyano group, halogen atom, alkyl group,alkenyl group, alkynyl group or halogenoalkyl group. Among others, it isparticularly preferred that the other group be a hydrogen atom, halogenatom, alkyl group or alkynyl group. In this case, the halogen atom ispreferably a fluorine, chlorine or bromine atom. As the alkyl group, ispreferred a methyl group. As the alkynyl group, is preferred an ethynylgroup. The position substituted by the halogen atom, alkyl group oralkynyl group is preferably a 6- or 7-position in the above formulathough it should not be particularly limited. As specific preferableexamples thereof, may be mentioned quinolinyl, isoquinolinyl andcinnolinyl groups. More preferred are 6-chloroquinolinyl,6-fluoroquinolinyl, 6-bromoquinolinyl, 6-ethynylquinolinyl,6-chloroisoquinolinyl, 6-fluoroisoquinolinyl, 6-bromoisoquinolinyl,6-ethynylisoquinolinyl, 7-chlorocinnolinyl, 7-fluorocinnolinyl,7-bromocinnolinyl and 7-ethynylcinnolinyl groups, with6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl,6-ethynylquinolin-2-yl, 6-chloroquinolin-3-yl, 6-fluoroquinolin-3-yl,6-bromoquinolin-3-yl, 6-ethynylquinolin-3-yl, 7-chloroquinolin-2-yl,7-fluoroquinolin-2-yl, 7-bromoquinolin-2-yl, 7-ethynylquinolin-2-yl,7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl,7-ethynylquinolin-3-yl, 6-chloroisoquinolin-3-yl,6-fluoroisoquinolin-3-yl, 6-bromoisoquinolin-3-yl,6-ethynylisoquinolin-3-yl, 7-chloroisoquinolin-3-yl,7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl,7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl,7-bromocinnolin-3-yl and 7-ethynylcinnolin-3-yl groups beingparticularly preferred. Among these, 6-chloroquinolin-2-yl,6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl,7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl,7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl,7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl,7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl,7-bromocinnolin-3-yl and 7-ethynylcinnolin-3-yl groups are furtherpreferred.

In the following group:

wherein numerals 5 to 8 indicate positions, X⁵ represents CH₂, CH, N orNH, Z¹ represents N, NH or O, Z² represents CH₂, CH, C or N, Z³represents CH₂, CH, S, SO₂ or C═O, X⁵-Z² indicates that X⁵ and Z² arebonded to each other by a single bond or double bond, and R²², R²³ andR²⁴ have the same meanings as defined above, numerals 5 to 8 indicatepositions, R²² and R²³ are, independently of each other, preferably ahydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group,alkynyl group or halogenoalkyl group. It is preferable that one of R²²and R²³ is a hydrogen, and the other is a hydrogen atom, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkylgroup. Among others, it is particularly preferred that the other groupbe a hydrogen atom, halogen atom, alkyl group or alkynyl group. In thiscase, the halogen atom is preferably a fluorine, chlorine or bromineatom. As the alkyl group, is preferred a methyl group. As the alkynylgroup, is preferred an ethynyl group. The position substituted by thehalogen atom, alkyl group or alkynyl group is preferably a 6- or7-position in the above formula though it should be not particularlylimited. R²⁴ is preferably a hydrogen atom or alkyl group, and a methylgroup is preferred as the alkyl group. As R²⁴, is particularly preferreda hydrogen atom. As specific preferable examples of the grouprepresented by the above formula, may be mentioned4-oxodihydroquinolinyl, tetrahydroquinolinyl,dihydroquinazolin-4-one-2-yl, 4-oxotetrahydrocinnolinyl,4-oxobenzopyranyl, 4-oxobenzothiadiazinyl,1,1-dioxy-4-oxo-benzothiadiazinyl and benzoxadiazinyl groups. Asspecific preferable examples thereof, may be mentioned6-chloro-4-oxodihydroquinolinyl, 6-fluoro-4-oxodihydroquinolinyl,6-bromo-4-oxodihydroquinolinyl, 6-ethynyl-4-oxodihydroquinolinyl,7-chloro-4-oxodihydroquinolinyl, 7-fluoro-4-oxodihydroquinolinyl,7-bromo-4-oxodihydroquinolinyl, 7-ethynyl-4-oxodihydroquinolinyl,6-chloro-4-oxo-1,4-dihydroquinazolinyl,6-fluoro-4-oxo-1,4-dihydroquinazolinyl,6-bromo-4-oxo-1,4-dihydroquinazolinyl,6-ethynyl-4-oxo-1,4-dihydroquinazolinyl,7-chloro-4-oxo-1,4-dihydroquinazolinyl,7-fluoro-4-oxo-1,4-dihydroquinazolinyl,7-ethynyl-4-oxo-1,4-dihydroquinazolinyl,6-chloro-1,2,3,4-tetrahydroquinolinyl,6-fluoro-1,2,3,4-tetrahydro-quinolinyl,6-bromo-1,2,3,4-tetrahydroquinolinyl,6-ethynyl-1,2,3,4-tetrahydroquinolinyl,7-chloro-1,2,3,4-tetrahydroquinolinyl,7-fluoro-1,2,3,4-tetrahydroquinolinyl,7-bromo-1,2,3,4-tetrahydroquinolinyl,7-ethynyl-1,2,3,4-tetrahydroquinolinyl,6-chloro-1,2,3,4-tetrahydro-4-oxocinnolinyl,6-fluoro-1,2,3,4-tetrahydro-4-oxocinnolinyl,6-bromo-1,2,3,4-tetrahydro-4-oxocinnolinyl,6-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolinyl,7-chloro-1,2,3,4-tetrahydro-4-oxocinnolinyl,7-fluoro-1,2,3,4-tetrahydro-4-oxocinnolinyl,7-bromo-1,2,3,4-tetrahydro-4-oxocinnolinyl,7-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolinyl,6-chloro-4H-4-oxobenzopyranyl, 6-fluoro-4H-4-oxobenzopyranyl,6-bromo-4H-4-oxobenzopyranyl, 6-ethynyl-4H-4-oxobenzopyranyl,7-chloro-4H-4-oxobenzopyranyl, 7-fluoro-4H-4-oxobenzopyranyl,7-bromo-4H-4-oxobenzopyranyl, 7-ethynyl-4H-4-oxobenzopyranyl,6-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,6-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,6-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,6-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,7-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,7-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,7-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,7-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,6-chloro-2H-1,2,4-benzoxadiazinyl, 6-fluoro-2H-1,2,4-benzoxadiazinyl,6-bromo-2H-1,2,4-benzoxadiazinyl, 6-ethynyl-2H-1,2,4-benzoxadiazinyl,7-chloro-2H-1,2,4-benzoxadiazinyl, 7-fluoro-2H-1,2,4-benzoxadiazinyl,7-bromo-2H-1,2,4-benzoxadiazinyl and 7-ethynyl-2H-1,2,4-benzoxadiazinylgroups; with 6-chloro-1,4-dihydroquinolin-4-one-2-yl,6-fluoro-1,4-dihydroquinolin-4-one-2-yl,6-bromo-1,4-dihydroquinolin-4-one-2-yl,6-ethynyl-1,4-dihydroquinolin-4-one-2-yl,7-chloro-1,4-dihydroquinolin-4-one-2-yl,7-fluoro-1,4-dihydroquinolin-4-one-2-yl,7-bromo-1,4-dihydroquinolin-4-one-2-yl,7-ethynyl-1,4-dihydroquinolin-4-one-2-yl,6-chloro-1,4-dihydroquinazolin-4-one-2-yl,6-fluoro-1,4-dihydroquinazolin-4-one-2-yl,6-bromo-1,4-dihydroquinazolin-4-one-2-yl,6-ethynyl-1,4-dihydroquinazolin-4-one-2-yl,7-chloro-1,4-dihydroquinazolin-4-one-2-yl,7-fluoro-1,4-dihydroquinazolin-4-one-2-yl,7-bromo-1,4-dihydroquinazolin-4-one-2-yl,7-ethynyl-1,4-dihydroquinazolin-4-one-2-yl,6-chloro-1,2,3,4-tetrahydroquinolin-2-yl,6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl,6-bromo-1,2,3,4-tetrahydroquinolin-2-yl,6-ethynyl-1,2,3,4-tetrahydroquinolin-2-yl,6-chloro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,6-fluoro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,6-bromo-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,6-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,7-chloro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,7-fluoro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,7-bromo-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,7-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,6-chloro-4H-4-oxobenzopyran-2-yl, 6-fluoro-4H-4-oxobenzopyran-2-yl,6-bromo-4H-4-oxobenzopyran-2-yl, 6-ethynyl-4H-4-oxobenzopyran-2-yl,7-chloro-4H-4-oxobenzopyran-2-yl, 7-fluoro-4H-4-oxobenzopyran-2-yl,7-bromo-4H-4-oxobenzopyran-2-yl, 7-ethynyl-4H-4-oxobenzopyran-2-yl,6-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,6-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,6-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,6-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,7-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,7-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,7-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,7-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,6-chloro-2H-1,2,4-benzoxadiazin-3-yl,6-fluoro-2H-1,2,4-benzoxadiazin-3-yl,6-bromo-2H-1,2,4-benzoxadiazin-3-yl,6-ethynyl-2H-1,2,4-benzoxadiazin-3-yl,7-chloro-2H-1,2,4-benzoxadiazin-3-yl,7-fluoro-2H-1,2,4-benzoxadiazin-3-yl,7-bromo-2H-1,2,4-benzoxadiazin-3-yl and7-ethynyl-2H-1,2,4-benzoxadiazin-3-yl groups being preferred. Amongthese, 6-chloro-1,4-dihydroquinolin-4-one-2-yl,6-fluoro-1,4-dihydroquinolin-4-one-2-yl,6-bromo-1,4-dihydroquinolin-4-one-2-yl,6-ethynyl-1,4-dihydroquinolin-4-one-2-yl,6-chloro-1,4-dihydroquinazolin-4-one-2-yl,6-fluoro-1,4-dihydroquinazolin-4-one-2-yl,6-bromo-1,4-dihydroquinazolin-4-one-2-yl and6-ethynyl-1,4-dihydroquinazolin-4-one-2-yl are particularly preferred.

In the following group:

wherein X⁶ represents O or S, R²⁵ and R²⁶ have the same meanings asdefined above, and numerals 5 to 8 indicate positions, X⁶ is preferablyO, and R²⁵ and R²⁶ are, independently of each other, preferably ahydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group,alkynyl group or halogenoalkyl group. It is preferable that one of R²⁵and R²⁶ is a hydrogen atom, and the other is a hydrogen atom, cyanogroup, halogen atom, alkyl group, alkenyl group, alkynyl group orhalogenoalkyl group. Among others, it is particularly preferred that theother group be a hydrogen atom, halogen atom, alkyl group or alkynylgroup. In this case, the halogen atom is preferably a fluorine, chlorineor bromine atom. As the alkyl group, is preferred a methyl group. As thealkynyl group, is preferred an ethynyl group. The position substitutedby the halogen atom, alkyl group or alkynyl group is preferably a 6- or7-position in the above formula though it should be not particularlylimited. As specific preferable examples thereof, may be mentioned6-chloro-2H-chromen-3-yl, 6-fluoro-2H-chromen-3-yl,6-bromo-2H-chromen-3-yl, 6-ethynyl-2H-chromen-3-yl,7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl,7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl groups, with7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl,7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl groups beingparticularly preferred.

In the following group:

wherein R²⁷ and R²⁸ have the same meanings as defined above, andnumerals 1 to 6 indicate positions, it is preferable that one of R²⁷ andR²⁸ is a hydrogen atom or halogen atom, and the other is a hydrogenatom, cyano group, nitro group, amino group, halogen atom, alkyl group,alkenyl group, alkynyl group, halogenoalkyl group orN,N-dialkylcarbamoyl group. Among others, it is particularly preferredthat the other group be a hydrogen atom, halogen atom, alkyl group oralkynyl group. In this case, the halogen atom is preferably a fluorine,chlorine or bromine atom. As the alkyl group, is preferred a methylgroup. As the alkynyl group, is particularly preferred an ethynyl group.As specific examples of the group represented by the above formula, maybe mentioned, chlorophenyl, fluorophenyl, bromophenyl, ethynylphenyl andchlorofluorophenyl groups. The position substituted by the halogen atom,alkyl group or alkynyl group in these groups is particularly preferablya 3- or 4-position in the above formula in the case of one substituentor a combination of a 4-position and a 2- or 3-position in the aboveformula in the case of two substituents though it should be notparticularly limited. As specific preferable examples thereof, may bementioned, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl,4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl,4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 2,4-dibromophenyl, 4-chloro-3-methylphenyl,4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl,4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl,4-bromo-2-methylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl and3,4-dibromophenyl.

In the following group:

wherein E¹, E², R²⁹ and R³⁰ have the same meanings as defined above, andnumerals 1 to 6 indicate positions, it is preferable that one of R²⁹ andR³⁰ is a hydrogen atom or halogen atom, and the other is a hydrogenatom, cyano group, halogen atom, alkyl group, alkenyl group, alkynylgroup or halogenoalkyl group. Among others, it is particularly preferredthat the other group be a hydrogen atom, halogen atom, alkyl group oralkynyl group. In this case, the halogen atom is preferably a fluorine,chlorine or bromine atom. As the alkyl group, is preferred a methylgroup. As the alkynyl group, is particularly preferred an ethynyl group.As specific examples of the group represented by the above formula, maybe mentioned pyridyl, pyrimidyl and pyridazinyl groups. The positionsubstituted by the halogen atom, alkyl group or alkynyl group in thesegroups is particularly preferably a 4- or 5-position in the aboveformula in the case where its bonding to the group T¹ is at a 2-positionin the above formula though it should be not particularly limited. Asspecific preferable examples thereof, may be mentioned 2-pyridyl,3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl,4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl,4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl,5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl,5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl,5-chloro-4-fluoro-2-pyridyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl,5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 5-chloro-2-pyrimidyl,5-fluoro-2-pyrimidyl, 5-bromo-2-pyrimidyl, 5-ethynyl-2-pyrimidyl,4-chloro-3-pyridazinyl, 4-fluoro-3-pyridazinyl, 4-bromo-3-pyridazinyl,4-ethynyl-3-pyridazinyl, 6-chloro-3-pyridazinyl, 6-fluoro-3-pyridazinyl,6-bromo-3-pyridazinyl and 6-ethynyl-3-pyridazinyl groups. Particularlypreferred are 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl,4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl,4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl,4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl,5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl,5-chloro-4-fluoro-2-pyridyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl,5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 6-chloro-3-pyridazinyl,6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl and6-ethynyl-3-pyridazinyl groups. Among these, 2-pyridyl, 3-pyridyl,4-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl,5-ethynyl-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl,4-chloro-5-fluoro-2-pyridyl, 4-chloro-3-pyridazinyl,4-fluoro-3-pyridazinyl, 4-bromo-3-pyridazinyl and4-ethynyl-3-pyridazinyl groups are further preferred.

In the following group:

wherein Y¹, Y², R³¹ and R³² have the same meanings as defined above, andnumerals 1 to 5 indicate positions, it is preferable that one of R³¹ andR³² is a hydrogen atom or halogen atom, and the other is a hydrogenatom, cyano group, halogen atom, alkyl group, alkenyl group, alkynylgroup or halogenoalkyl group. Among others, it is particularly preferredthat the other group be a hydrogen atom, halogen atom, alkyl group oralkynyl group. In this case, the halogen atom is preferably a fluorine,chlorine or bromine atom. As the alkyl group, is preferred a methylgroup. As the alkynyl group, is particularly preferred an ethynyl group.As specific examples of the group represented by the above formula, maybe mentioned thienyl, pyrrolyl, furyl, oxazolyl and thiazolyl groups.The position substituted by the halogen atom, alkyl group or alkynylgroup in these groups is particularly preferably a 4- or 5-position inthe above formula though it should be not particularly limited. Asspecific preferable examples thereof, may be mentioned4-chloro-2-thienyl, 4-fluoro-2-thienyl, 4-bromo-2-thienyl,4-ethynyl-2-thienyl, 4-chloro-2-pyrrolyl, 4-fluoro-2-pyrrolyl,4-bromo-2-pyrrolyl, 4-ethynyl-2-pyrrolyl, 4-chloro-2-furyl,4-fluoro-2-furyl, 4-bromo-2-furyl, 4-ethynyl-2-furyl,5-chloro-2-thienyl, 5-fluoro-2-thienyl, 5-bromo-2-thienyl,5-ethynyl-2-thienyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl,5-bromo-2-thiazolyl, 5-ethynyl-2-thiazolyl, 5-chloro-2-oxazolyl,5-fluoro-2-oxazolyl, 5-bromo-2-oxazolyl and 5-ethynyl-2-oxazolyl groups.Particularly preferred are 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl,5-bromo-2-thiazolyl and 5-ethynyl-2-thiazolyl groups.

In the following group:

wherein numerals 1 to 8 indicate positions, each N indicates that anyone of 4 carbon atoms at positions 1 to 4 and any one of 4 carbon atomsat positions 5 to 8 have been substituted by a nitrogen atom, and R³⁴ toR³⁶ have the same meanings as defined above, the position of eachnitrogen atom may be in any positional relation, and R³⁴ is preferably ahydrogen atom or halogen atom. It is preferable that one of R³⁵ and R³⁶is a hydrogen atom or halogen atom, and the other is a hydrogen atom,cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group orhalogenoalkyl group. Among others, it is particularly preferred that theother group be a hydrogen atom, halogen atom, alkyl group or alkynylgroup. In this case, the halogen atom is preferably a fluorine, chlorineor bromine atom. As the alkyl group, is preferred a methyl group. As thealkynyl group, is preferred an ethynyl group. The position substitutedby the halogen atom, alkyl group or alkynyl group is not be particularlylimited. As preferable examples of specific groups represented by theabove formula, may be mentioned 6-chloro-1,5-naphthyridin-2-yl,6-fluoro-1,5-naphthyridin-2-yl, 6-bromo-1,5-naphthyridin-2-yl,6-ethynyl-1,5-naphthyridin-2-yl, 7-chloro-1,5-naphthyridin-2-yl,7-fluoro-1,5-naphthyridin-2-yl, 7-bromo-1,5-naphthyridin-2-yl,7-ethynyl-1,5-naphthyridin-2-yl, 6-chloro-1,5-naphthyridin-3-yl,6-fluoro-1,5-naphthyridin-3-yl, 6-bromo-1,5-naphthyridin-3-yl,6-ethynyl-1,5-naphthyridin-3-yl, 7-chloro-1,5-naphthyridin-3-yl,7-fluoro-1,5-naphthyridin-3-yl, 7-bromo-1,5-naphthyridin-3-yl,7-ethynyl-1,5-naphthyridin-3-yl, 6-chloro-1,7-naphthyridin-2-yl,6-fluoro-1,7-naphthyridin-2-yl, 6-bromo-1,7-naphthyridin-2-yl,6-ethynyl-1,7-naphthyridin-2-yl, 6-chloro-1,7-naphthyridin-3-yl,6-fluoro-1,7-naphthyridin-3-yl, 6-bromo-1,7-naphthyridin-3-yl,6-ethynyl-1,7-naphthyridin-3-yl, 6-chloro-1,8-naphthyridin-2-yl,6-fluoro-1,8-naphthyridin-2-yl, 6-bromo-1,8-naphthyridin-2-yl,6-ethynyl-1,8-naphthyridin-2-yl, 7-chloro-1,8-naphthyridin-2-yl,7-fluoro-1,8-naphthyridin-2-yl, 7-bromo-1,8-naphthyridin-2-yl,7-ethynyl-1,8-naphthyridin-2-yl, 6-chloro-1,8-naphthyridin-3-yl,6-fluoro-1,8-naphthyridin-3-yl, 6-bromo-1,8-naphthyridin-3-yl,6-ethynyl-1,8-naphthyridin-3-yl, 7-chloro-1,8-naphthyridin-3-yl,7-fluoro-1,8-naphthyridin-3-yl, 7-bromo-1,8-naphthyridin-3-yl,7-ethynyl-1,8-naphthyridin-3-yl, 6-chloro-2,5-naphthyridin-3-yl,6-fluoro-2,5-naphthyridin-3-yl, 6-bromo-2,5-naphthyridin-3-yl,6-ethynyl-2,5-naphthyridin-3-yl, 7-chloro-2,5-naphthyridin-3-yl,7-fluoro-2,5-naphthyridin-3-yl, 7-bromo-2,5-naphthyridin-3-yl,7-ethynyl-2,5-naphthyridin-3-yl, 7-chloro-2,6-naphthyridin-3-yl,7-fluoro-2,6-naphthyridin-3-yl, 7-bromo-2,6-naphthyridin-3-yl,7-ethynyl-2,6-naphthyridin-3-yl, 6-chloro-2,8-naphthyridin-3-yl,6-fluoro-2,8-naphthyridin-3-yl, 6-bromo-2,8-naphthyridin-3-yl,6-ethynyl-2,8-naphthyridin-3-yl, 7-chloro-2,8-naphthyridin-3-yl,7-fluoro-2,8-naphthyridin-3-yl, 7-bromo-2,8-naphthyridin-3-yl and7-ethynyl-2,8-naphthyridin-3-yl groups. Particularly preferable examplethereof include 7-chloro-2,5-naphthyridin-3-yl,7-fluoro-2,5-naphthyridin-3-yl, 7-bromo-2,5-naphthyridin-3-yl,7-ethynyl-2,5-naphthyridin-3-yl.

In addition to the above-mentioned 12 groups (a) to (1), athienopyrrolyl group which may be substituted is preferred. This groupmay have 1 to 3 substituents, and examples of the substituents include ahydroxyl group, a nitro group, an amino group, a cyano group, halogenatoms, alkyl groups, alkenyl groups, alkynyl groups, halagenoalkylgroups, hydroxyalkyl groups, alkoxy groups, alkoxyalkyl groups, acarboxyl group, carboxyalkyl groups, acyl groups, a carbamoyl group,N-alkylcarbamoyl groups, N,N-dialkylcarbamoyl groups, alkoxycarbonylgroups, an amidino group and alkoxycarbonylalkyl groups. Among these, acyano group, halogen atoms, alkyl groups, alkenyl groups alkynyl groupsand halogenoalkyl groups are preferred. As specific preferable examplesthereof, may be mentioned 2-chlorothieno[2,3-b]pyrrol-5-yl,2-fluorothieno[2,3-b]pyrrol-5-yl, 2-bromothieno[2,3-b]pyrrol-5-yl, and2-ethynylthieno[2,3-b]pyrrol-5-yl groups.

<On Group Q¹>

In the present invention, Q¹ means a saturated or unsaturated, 5- or6-membered cyclic hydrocarbon group which may be substituted, asaturated or unsaturated, 5- to 7-membered heterocyclic group which maybe substituted, a saturated or unsaturated, bicyclic or tricyclic fusedhydrocarbon group which may be substituted, or a saturated orunsaturated, bicyclic or tricyclic fused heterocyclic group which may besubstituted.

As examples of the saturated or unsaturated, 5- or 6-membered cyclichydrocarbon group, may be mentioned cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl and phenyl groups. Cyclopentyl, cyclohexyl andphenyl groups are preferred, with a phenyl group being particularlypreferred.

The saturated or unsaturated, 5- to 7-membered heterocyclic group meansa monovalent heterocyclic group having at least one hetero atom selectedfrom oxygen, sulfur and nitrogen atoms, and examples thereof may includefuryl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,oxazolinyl, thiazolyl, thiazolinyl, thiadiazolyl, furazanyl, pyranyl,pyridyl, pyrimidyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl,oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl,thiomorpholinyl, tetrazolyl, triazolyl, triazinyl, azepinyl, diazepinyland triazepinyl groups. Thienyl, pyrazolyl, imidazolyl, oxazolyl,thiazolyl, thiadiazolyl, furazanyl, pyridyl, pyrimidyl, pyridazinyl,pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, thiadiazinyl andtriazolyl groups are preferred, with thienyl, thiazolyl, pyrazolyl,imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolidinyl, piperazinyland piperidinyl groups being particularly preferred. Of theseheterocyclic groups, the nitrogen-containing heterocyclic groups may bein the form of an N-oxide.

The saturated or unsaturated, bicyclic or tricyclic fused hydrocarbongroup means the same saturated or unsaturated, bicyclic or tricyclicfused hydrocarbon group as described in the description of Q⁴ in thegeneral formula (1). As specific examples thereof, may be mentionedindenyl, indanyl, naphthyl, tetrahydronaphthyl, anthryl and phenanthrylgroups, with indenyl, indanyl, naphthyl and tetrahydronaphthyl groupsbeing preferred.

The saturated or unsaturated, bicyclic or tricyclic fused heterocyclicgroup means the same saturated or unsaturated, bicyclic or tricyclicfused heterocyclic group as described in the description of Q⁴ in thegeneral formula (1). As specific examples thereof, may be mentionedbenzofuryl, isobenzofuryl, benzothienyl, indolyl, indolinyl, isoindolyl,isoindolinyl, indazolyl, quinolyl, dihydroquinolyl, 4-oxodihydroquinolyl(dihydroquinon-4-on), tetrahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, chromenyl, chromanyl, isochromanyl,4H-4-oxobenzopyranyl, 3,4-dihydro-4H-4-oxobenzopyranyl, 4H-quinolizinyl,quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalyl,tetrahydroquinoxalyl, cinnolinyl, tetrahydrocinnolinyl, indolizinyl,tetrahydroindolizinyl, benzothiazolyl, tetrahydrobenzothiazolyl,benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, benzimidazoyl,naphthyridinyl, tetrahydronaphthyridinyl, thienopyridyl,tetrahydrothienopyridyl, thiazolopyridyl, tetrahydrothiazolopyridyl,thiazolopyridazinyl, tetrahydrothiazolopyridazinyl, pyrrolopyridyl,dihydropyrrolopyridyl, tetrahydropyrrolopyridyl, pyrrolopyrimidinyl,dihydropyrrolopyrimidinyl, pyridoquinazolyl, dihydropyridoquinazolyl,pyridopyrimidinyl, tetrahydropyridopyrimidinyl, pyranothiazolyl,dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridyl,oxazolopyridyl, tetrahydrooxazolopyridyl, oxazolopyridazinyl,tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl,pyrrolooxazolyl, dihydropyrrolooxazolyl, thienopyrrolyl,thiazolopyrimidinyl, dihydrothiazolopyrimidinyl,4-oxotetrahydrocinnolinyl, 1,2,4-benzothiadiazinyl,1,1-dioxy-2H-1,2,4-benzothiadiazinyl, 1,2,4-benzoxadiazinyl,cyclopentapyranyl, thienofuranyl, furopyranyl, pyridoxazinyl,pyrazoloxazolyl, imidazothiazolyl, imidazopyridyl,tetrahydroimidazopyridyl, pyrazinopyridazinyl, benzisoquinolyl,furocinnolyl, pyrazolothiazolopyridazinyl,tetrahydropyrazolothiazolopyridazinyl,hexahydrothiazolopyridazinopyridazinyl, imidazotriazinyl,oxazolopyridyl, benzoxepinyl, benzoazepinyl, tetrahydrobenzoazepinyl,benzodiazepinyl, benzotriazepinyl, thienoazepinyl,tetrahydrothienoazepinyl, thienodiazepinyl, thienotriazepinyl,thiazoloazepinyl, tetrahydrothiazoloazepinyl,4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups. Preferredare benzothiazolyl, tetrahydrobenzothiazolyl, thienopyridyl,tetrahydrothienopyridyl, thienopyrrolyl, thiazolopyridyl,tetrahydrothiazolopyridyl, thiazolopyridazinyl,tetrahydrothiazolopyridazinyl, pyrrolopyrimidinyl,dihydropyrrolopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl,furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl,tetrahydrooxazolopyridyl, pyrrolopyridyl, dihydropyrrolopyridyl,tetrahydropyrrolopyridyl, oxazolopyridazinyl,tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl,pyrrolooxazolyl, dihydropyrrolooxazolyl, thiazolopyrimidinyl,dihydrothiazolopyrimidinyl, benzoazepinyl, tetrahydrobenzoazepinyl,thiazoloazepinyl, tetrahydrothiazoloazepinyl, thienoazepinyl,tetrahydrothienoazepinyl,4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups, withtetrahydrobenzothiazolyl, tetrahydrothienopyridyl,tetrahydrothiazolopyridyl, tetrahydrothiazolopyridazinyl,dihydropyrrolopyrimidinyl, dihydropyranothiazolyl,tetrahydrooxazolopyridyl, dihydropyrrolothiazolyl,4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups beingparticularly preferred.

No particular limitation is imposed on the fusing form of the fusedheterocyclic groups. For example, thienopyridine may be any ofthieno[2,3-b]pyridine, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine,thieno-[3,2-c]pyridine, thieno[3,4-b]pyridine and thieno[3,4-c]pyridine,with thieno[2,3-c]pyridine and thieno[3,2-c]pyridine being preferred.Thienopyrrolyl may be any of thieno[2,3-b]pyrrolyl andthieno[3,2-b]-pyrrolyl. Thiazolopyridine may be any ofthiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine,thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine,thiazolo[3,4-a]pyridine and thiazolo[3,2-a]pyridine, withthiazolo[4,5-c]pyridine and thiazolo[5,4-c]pyridine being preferred.Thiazolopyridazine may be any of thiazolo-[4,5-c]pyridazine,thiazolo[4,5-d]pyridazine, thiazolo[5,4-c]pyridazine andthiazolo[3,2-b]pyridazine, with thiazolo[4,5-d]pyridazine beingpreferred. Pyrrolopyridine may be any of pyrrolo[2,3-b]pyridine,pyrrolo[2,3-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,4-b]pyridine and pyrrolo[3,4-c]pyridine, withpyrrolo[2,3-c]pyridine and pyrrolo[3,2-c]pyridine being preferred.Pyrrolopyrimidine may be any of pyrrolo[3,4-d]pyrimidine,pyrrolo[3,2-d]pyrimidine and pyrrolo[2,3-d]pyrimidine, withpyrrolo[3,4-d]pyrimidine being preferred. Pyridopyrimidine may be any ofpyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine,pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine,pyrido[1,2-c]pyrimidine and pyrido[1,2-a]pyrimidine, withpyrido[3,4-d]pyrimidine and pyrido[4,3-d]pyrimidine being preferred.Pyranothiazole may be any of pyrano[2,3-d]thiazole,pyrano[4,3-d]thiazole, pyrano[3,4-d]thiazole and pyrano[3,2-d]thiazole,with pyrano[4,3-d]thiazole and pyrano[3,4-d]thiazole being preferred.Furopyridine may be any of furo[2,3-b]pyridine, furo[2,3-c]pyridine,furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[3,4-b]pyridine andfuro[3,4-c]pyridine, with furo[2,3-c]pyridine and furo[3,2-c]pyridinebeing preferred. Oxazolopyridine may be any of oxazolo[4,5-b]pyridine,oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine,oxazolo[3,4-a]pyridine and oxazolo[3,2-a]pyridine, withoxazolo[4,5-c]pyridine and oxazolo[5,4-c]pyridine being preferred.Oxazolopyridazine may be any of oxazolo[4,5-c]pyridazine,oxazolo[4,5-d]pyridazine, oxazolo[5,4-c]pyridazine andoxazolo[3,4-b]pyridazine, with oxazolo[4,5-d]pyridazine being preferred.Pyrrolothiazole may be any of pyrrolo[2,1-b]thiazole,pyrrolo[1,2-c]thiazole, pyrrolo[2,3-d]thiazole, pyrrolo[3,2-d]thiazoleand pyrrolo[3,4-d]thiazole, with pyrrolo[3,4-d]thiazole being preferred.Pyrrolooxazole may be any of pyrrolo[2,1-b]oxazole,pyrrolo[1,2-c]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole andpyrrolo[3,4-d]oxazole, with pyrrolo[3,4-d]oxazole being preferred.Benzoazepine may be any of 1H-1-benzoazepine, 1H-2-benzoazepine and1H-3-benzoazepine, with 1H-3-benzoazepine being preferred.Thiazolo[4,5-c]azepine may be any of 4H-thiazolo[4,5-c]azepine,4H-thiazolo[4,5-d]azepine and 4H-thiazolo[5,4-c]azepine, with4H-thiazolo[4,5-d]azepine being preferred. Thieno[2,3-c]azepine may beany of 4H-thieno[2,3-d]azepine and 4H-thieno[3,2-c]azepine, with4H-thieno[2,3-d]azepine being preferred.

Of these heterocyclic groups, the nitrogen-containing heterocyclicgroups may be in the form of an N-oxide. Incidentally, the position ofthe above substituent group bonded to Q² is not particularly limited.

The above-described saturated or unsaturated, 5- or 6-membered cyclichydrocarbon groups, saturated or unsaturated, 5- to 7-memberedheterocyclic groups, saturated or unsaturated, bicyclic or tricyclicfused hydrocarbon groups and saturated or unsaturated, bicyclic ortricyclic fused heterocyclic groups may each have 1 to 3 substituents.Examples of the substituents may include a hydroxyl group; halogen atomsof fluorine atom, chlorine atom, bromine atom and iodine atom;halogenomethyl groups having 1 to 3 halogen atoms; an amino group; acyano group; an amidino group; a hydroxyamidino group; linear, branchedor cyclic alkyl groups having 1 to 6 carbon atoms (hereinafter referredto as C₁-C₆ alkyl groups which mean linear, branched and cyclic alkylgroups; for example, linear or branched C₁-C₆ alkyl groups such asmethyl group, ethyl group, isopropyl group and tert-butyl group; C₃-C₆cycloalkyl groups such as cyclopropyl group, cyclobutyl group,cyclopentyl group and 1-methylcyclopropyl group; and C₃-C₆cycloalkyl-C₁-C₆ alkyl groups such as cyclopropylmethyl group);hydroxy-C₁-C₆ alkyl groups (such as hydroxyethyl and1,1-dimethyl-2-hydroxyethyl groups); C₁-C₆ alkoxy groups (for example,methoxy group, ethoxy group and the like); C₁-C₆ alkoxy-C₁-C₆ alkylgroups; a carboxyl group; C₂-C₆ carboxyalkyl groups (for example,carboxymethyl group and the like); C₂-C₆ alkoxycarbonyl-C₁-C₆ alkylgroups (for example, methoxycarbonylmethyl group,tert-butoxycarbonylmethyl group and the like); amidino groupssubstituted by a C₂-C₆ alkoxycarbonyl group; C₂-C₆ alkenyl groups (forexample, vinyl group, allyl group and the like); C₂-C₆ alkynyl groups(for example, ethynyl group, propynyl group and the like); C₂-C₆alkoxycarbonyl groups (for example, methoxycarbonyl group,ethoxycarbonyl group, tert-butoxycarbonyl group and the like); aminoC₁-C₆ alkyl groups (for example, aminomethyl group, aminoethyl group andthe like); C₁-C₆ alkylamino-C₁-C₆ alkyl groups (for example,N-methylaminomethyl group, N-ethylaminomethyl group and the like);di(C₁-C₆ alkyl)amino-C₁-C₆ alkyl groups (for example,N,N-dimethylaminomethyl group, N,N-diethylaminomethyl group,N-ethyl-N-methylaminoethyl group and the like); C₂-C₆alkoxycarbonylamino-C₁-C₆ alkyl groups (for example,methoxycarbonylaminoethyl group, tert-butoxycarbonylaminoethyl group andthe like); C₁-C₆ alkanoyl groups (for example, formyl group, acetylgroup, methylpropionyl group, cyclopentanecarbonyl group and the like);C₁-C₆ alkanoylamino-C₁-C₆ alkyl groups (for example, acetylaminomethylgroup and the like); C₁-C₆ alkylsulfonyl groups (for example,methanesulfonyl group and the like); C₁-C₆ alkylsulfonylamino-C₁-C₆alkyl groups (for example, methanesulfonylaminomethyl group and thelike); a carbamoyl group; C₁-C₆ alkylcarbamoyl groups (for example,methylcarbamoyl group, ethylcarbamoyl group, isopropylcarbamoyl group,tert-butylcarbamoyl group and the like); N,N-di(C₁-C₆ alkyl)carbamoylgroups (for example, dimethylcarbamoyl group, diethylcarbamoyl group,methylethylcarbamoyl group and the like); C₁-C₆ alkylamino groups (forexample, N-methylamino group, N-ethylamino group and the like); di(C₁-C₆alkyl)amino groups (for example, N,N-dimethylamino group,N,N-diethylamino group, N-ethyl-N-methylamino group and the like); 5- or6-membered heterocyclic groups containing one of nitrogen, oxygen andsulfur or the same or different two atoms thereof (for example,pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinylgroup, pyridyl group, pyrimidinyl group, tetrahydropyranyl group and thelike); the above 5- or 6-membered heterocyclic-C₁-C₄ alkyl groups (forexample, morpholinomethyl group and the like); and the above 5- or6-membered heterocyclic-amino-C₁-C₄ alkyl groups (for example,N-(oxazol-2-yl)aminomethyl group and the like).

As specific examples of Q¹, may be mentioned bicyclic heterocyclicgroups such as 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-carboxymethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-butyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl,5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl,5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl,5,7-dihydro-6-methylpyrrolo[3,4-d]pyrimidin-2-yl,5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl,5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[4,5-d]pyridazin-2-yl,5-dimethylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl,5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl and6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl groups; and 5- or 6-memberedheterocyclic groups such as pyridyl groups such as 4-pyridyl and2-pyridyl; dihydrooxazolyl groups such as 4,5-dihydrooxazol-2-yl;4-[N-(4,5-dihydrooxazol-2-yl)-N-methylaminomethyl]thiophen-2-yl,4-[N-(4,5-dihydrooxazol-2-yl)-N-methylaminomethyl]-3-chlorothiophen-2-yl,5-(N-methylaminomethyl)thiazol-2-yl,5-(N-methylaminomethyl)thiophen-2-yl,5-(N,N-dimethylaminomethyl)thiazol-2-yl,5-(N,N-dimethylaminomethyl)thiophen-2-yl and5-(N,N-dimethylaminomethyl)pyridin-2-yl groups. Incidentally, Q¹ is notlimited by these examples at all.

<On Group Q²>

The group Q² means a single bond, a saturated or unsaturated, 5- or6-membered divalent cyclic hydrocarbon group which may be substituted, asaturated or unsaturated, 5- to 7-membered divalent heterocyclic groupwhich may be substituted, a saturated or unsaturated, divalent bicyclicor tricyclic fused hydrocarbon group which may be substituted, or asaturated or unsaturated, divalent bicyclic or tricyclic fusedheterocyclic group which may be substituted.

In the group Q², the saturated or unsaturated, 5- or 6-membered divalentcyclic hydrocarbon group means a divalent group derived from thesaturated or unsaturated, 5- or 6-membered cyclic hydrocarbon describedin the description of Q⁴ in the general formula (1). As specificexamples thereof, may be mentioned cyclohexylene, cyclohexenylene andphenylene groups, with cyclohexylene and phenylene groups beingpreferred.

The saturated or unsaturated, 5- to 7-membered divalent heterocyclicgroup means a divalent group derived from the saturated or unsaturated,5- to 7-membered heterocyclic ring described in the description of Q⁴ inthe general formula (1). As specific examples thereof, may be mentioneddivalent groups derived from furan, pyrrole, thiophene, pyrazole,imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazane,pyrane, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine,piperidine, oxazine, oxadiazine, morpholine, thiazine, thiadiazine,thiomorpholine, tetrazole, triazole, triazine, azepien, diazepine andtriazepine. Among these, preferable examples thereof include divalentgroups derived from pyrazole, imidazole, oxazole, thiazole, thiadiazole,furazane, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine,piperidine, triazole, triazine, azepien, diazepine and triazepine.

The saturated or unsaturated, divalent bicyclic or tricyclic fusedhydrocarbon means a divalent group derived from the saturated orunsaturated, bicyclic or tricyclic fused hydrocarbon group described inthe description of Q⁴ in the general formula (1). As specific examplesthereof, may be mentioned divalent groups derived from indene, indane,naphthalene, tetrahydronaphthalene, anthracene, phenanthrene and thelike. As preferable examples thereof, may be mentioned divalent groupsderived from indane and naphthalene.

The saturated or unsaturated, divalent bicyclic or tricyclic fusedheterocyclic group means a divalent group derived from the saturated orunsaturated, bicyclic or tricyclic fused heterocyclic ring described inthe description of Q⁴ in the general formula (1). As specific examplesthereof, may be mentioned divalent groups derived from benzofuran,benzothiophene, indole, isoindole, indazole, quinoline,tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, quinazoline,dihydroquinazoline, tetrahydroquinazoline, quinoxaline,tetrahydroquinoxaline, cinnoline, tetrahydrocinnoline, indolizine,tetrahydroindolizine, benzothiazole, tetrahydrobenzothiazole,naphthyridine, tetrahydronaphthyridine, thienopyridine,tetrahydrothienopyridine, thiazolopyridine, tetrahydrothiazolopyridine,thiazolopyridazine, tetrahydrothiazolopyridazine, pyrrolopyridine,dihydropyrrolopyridine, tetrahydropyrrolopyridine, pyrrolopyrimidine,dihydropyrrolopyrimidine, dihydropyridoquinazoline, pyranothiazole,dihydropyranothiazole, furopyridine, tetrahydrofuropyridine,oxazolopyridine, tetrahydrooxazolopyridine, oxazolopyridazine,tetrahydrooxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole,pyrrolooxazole, dihydropyrrolooxazole and benzoazepine. As preferableexamples thereof, may be mentioned divalent groups derived frombenzofuran, benzothiophene, indole, indazole, quinoline, isoquinoline,tetrahydroisoquinoline, benzothiazole, naphthyridine, thienopyridine,thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine,pyrrolopyridine, tetrahydropyrrolopyridine, pyridopyrimidine,pyranothiazole, dihydropyranothiazole, furopyridine, oxazolopyridine,oxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole,pyrrolooxazole and dihydropyrrolooxazole. No particular limitation isimposed on the fusing form of the fused heterocyclic group. For example,naphthyridine may be any of 1,5-, 1,6-, 1,7-, 1,8-, 2,6- and2,7-naphthyridine, thienopyridine may be any of thieno[2,3-b]pyridine,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[3,2-c]pyridine,thieno-[3,4-b]pyridine and thieno[3,4-c]pyridine, thiazolopyridine maybe any of thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine,thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine,thiazolo[3,4-a]pyridine and thiazolo[3,2-a]pyridine, thiazolopyridazinemay be any of thiazolo[4,5-c]pyridazine, thiazolo[4,5-d]pyridazine,thiazolo[5,4-c]pyridazine and thiazolo[3,2-b]pyridazine, pyrrolopyridinemay be any of pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,4-b]pyridineand pyrrolo[3,4-c]pyridine, pyrrolopyrimidine may be any ofpyrrolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine andpyrrolo[2,3-d]pyrimidine, pyridopyrimidine may be any ofpyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine andpyrido[3,4-d]pyrimidine, pyranothiazole may be any ofpyrano[2,3-d]thiazole, pyrano[4,3-d]thiazole, pyrano-[3,4-d]thiazole andpyrano[3,2-d]thiazole, furopyridine may be any of furo[2,3-b]pyridine,furo[2,3-c]pyridine, furo[3,2-b]pyridine, furo[3,2-c]pyridine,furo[3,4-b]pyridine and furo[3,4-c]pyridine, oxazolopyridine may be anyof oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine,oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, oxazolo[3,4-a]pyridineand oxazolo[3,2-a]pyridine, oxazolopyridazine may be any ofoxazolo[4,5-c]pyridazine, oxazolo[4,5-d]pyridazine,oxazolo[5,4-c]pyridazine and oxazolo[3,4-b]pyridazine, pyrrolothiazolemay be any of pyrrolo[2,1-b]thiazole, pyrrolo[1,2-c]thiazole,pyrrolo[3,2-d]thiazole and pyrrolo[3,4-d]thiazole, and pyrrolooxazolemay be any of pyrrolo[2,1-b]oxazole, pyrrolo[1,2-c]oxazole,pyrrolo[2,3-d]oxazole, pyrrolo-[3,2-d]oxazole and pyrrolo[3,4-d]oxazole.Other fusing forms than these may be allowed.

The above-described saturated or unsaturated, 5- or 6-membered divalentcyclic hydrocarbon groups, saturated or unsaturated, 5- to 7-membereddivalent heterocyclic groups, saturated or unsaturated, divalentbicyclic or tricyclic fused hydrocarbon groups and saturated orunsaturated, divalent bicyclic or tricyclic fused heterocyclic groupsmay each have 1 to 3 substituents. Examples of the substituents mayinclude a hydroxyl group, halogen atoms of a fluorine, chlorine, bromineand iodine atoms, halogenoalkyl groups having 1 to 3 halogen atoms, anamino group, a cyano group, aminoalkyl groups, an amidino group, ahydroxyamidino group, linear, branched or cyclic alkyl groups having 1to 6 carbon atoms (for example, methyl group, ethyl group, etc.),linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms (forexample, methoxy group, ethoxy group, etc.), an amidino groupsubstituted by a linear, branched or cyclic alkoxycarbonyl groups having2 to 7 carbon atoms (for example, methoxycarbonylamidino group,ethoxycarbonylamidino group, etc.), linear, branched or cyclic alkenylgroups having 2 to 6 carbon atoms (for example, vinyl group, allylgroup, etc.), linear or branched alkynyl groups having 2 to 6 carbonatoms (for example, ethynyl group, propynyl group, etc.), linear,branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms (forexample, methoxycarbonyl group, ethoxycarbonyl group, etc.), and acarbamoyl group.

Preferable groups in Q² described above are a single bond, saturated orunsaturated, 5- or 6-membered divalent cyclic hydrocarbon groups whichmay be substituted, saturated or unsaturated, 5- to 7-membered divalentheterocyclic groups which may be substituted, and saturated orunsaturated, divalent bicyclic or tricyclic fused heterocyclic groupswhich may be substituted. In particular, a single bond, saturated orunsaturated, divalent 5- or 6-membered cyclic hydrocarbon groups,saturated or unsaturated, 5- to 7-membered divalent heterocyclic groupsare preferred.

When Q¹ is a saturated or unsaturated, bicyclic or tricyclic fusedhydrocarbon group which may be substituted, or a saturated orunsaturated, bicyclic or tricyclic fused heterocyclic group which may besubstituted, the group Q² is preferably a single bond. The case where Q²is a single bond in the above-described combination means that thegeneral formula (1):

Q¹-Q²-T⁰-N(R¹)-Q³-N(R²)-T¹-Q⁴  (1)

wherein R¹, R², Q¹, Q², Q³, Q⁴, T⁰ and T¹ have the same meanings asdefined above, comes to the following general formula (1′):

Q¹-T⁰-N(R¹)-Q³-N(R²)-T¹-Q²  (1′)

wherein Q¹ represents the above bicyclic or tricyclic fused hydrocarbongroup or bicyclic or tricyclic fused heterocyclic group, and R¹, R², Q³,Q⁴, T⁰ and T¹ have the same meanings as defined above.

Specifically, are preferred those in which the group Q¹ is athienopyridyl group which may be substituted; a tetrahydrothienopyridylgroup which may be substituted; a thiazolopyridyl group which may besubstituted; a tetrahydrothiazolopyridyl group which may be substituted;a thiazolopyridazinyl group which may be substituted; atetrahydrothiazolopyridazinyl group which may be substituted; apyranothiazolyl group which may be substituted; a dihydropyranothiazolylgroup which may be substituted; a furopyridyl group which may besubstituted; a tetrahydrofuropyridyl group which may be substituted; anoxazolopyridyl group which may be substituted; atetrahydrooxazolopyridyl group which may be substituted; apyrrolopyridyl group which may be substituted; a dihydropyrrolopyridylgroup which may be substituted; a tetrahydropyrrolopyridyl group whichmay be substituted; a pyrrolopyrimidinyl group which may be substituted;a dihydropyrrolopyrimidinyl group which may be substituted; anoxazolopyridazinyl group which may be substituted; atetrahydrooxazolopyridazinyl group which may be substituted; apyrrolothiazolyl group which may be substituted; adihydropyrrolothiazolyl group which may be substituted; apyrrolooxazolyl group which may be substituted; a dihydropyrrolooxazolylgroup which may be substituted; a benzothiazolyl group which may besubstituted; a tetrahydrobenzothiazolyl group which may be substituted;a thiazolopyrimidinyl which may be substituted; adihydrothiazolepyrimidinyl which may be substituted; a benzoazepinylwhich may be substituted; a tetrahydrobenzoazepinyl which may besubstituted; a thiazoloazepinyl which may be substituted; atetrahydrothiazoloazepinyl which may be substituted; a thienoazepinylwhich may be substituted; a tetrahydrothienoazepinyl which may besubstituted; a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinylgroup which may be substituted; or a5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which maybe substituted, and Q² is a single bond.

When Q¹ is a saturated or unsaturated, 5- or 6-membered cyclichydrocarbon group which may be substituted, or a saturated orunsaturated, 5- to 7-membered heterocyclic group which may besubstituted, the group Q² is preferably a saturated or unsaturated, 5-or 6-membered divalent cyclic hydrocarbon group which may besubstituted, or a saturated or unsaturated, 5- to 7-membered divalentheterocyclic group which may be substituted. As preferable example ofthe group Q¹-Q², may be mentioned 4-(4-pyridyl)phenyl,4-(2-pyridyl)phenyl, 5-(4-pyridyl)thiazolyl, 1-(4-pyridyl)piperidyl,4-(4-pyridyl)piperidyl, 4-hydroxy-1-(4-pyridyl)piperidin-4-yl,biphenylyl, 4-(2-aminosulfonylphenyl)phenyl, 4-(2-amidinophenyl)phenyl,4-(2-methylsulfonylphenyl)phenyl, 4-(2-aminomethylphenyl)phenyl,4-(2-carbamoylphenyl)phenyl, 4-(2-imidazolyl)phenyl,4-(1-methyl-2-imidazolyl)phenyl,4-(2,3,4,5-tetrahydropyrimidin-2-yl)phenyl,4-(1-methyl-2,3,4,5-tetrahydropyrimidin-2-yl)phenyl,4-(5-tetrazolyl)phenyl, 1-(4-pyridyl)piperidin-4-yl,3-(4-piperidyl)isoxazolin-5-yl, 3-(4-amidinophenyl)isoxazolin-5-yl,3-(4-piperidyl)isoxazolidin-5-yl, 3-(4-amidinophenyl)isoxazolidin-5-yl,2-(4-piperidyl)-1,3,4-thiadiazol-5-yl,2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl, 4-(4-piperidyl)piperidin-1-yl,4-(4-piperidyl)piperazin-1-yl, 4-(4-piperazinyl)piperazin-1-yl,1-(4-pyrimidinyl)piperidin-1-yl,1-(2-methylpyrimidin-4-yl)piperidin-4-yl,1-(4-pyrimidinyl)pyrrolidin-3-yl,1-(4-methylpyrimidin-6-yl)piperazin-4-yl,1-(2-methylpyrimidin-4-yl)pyrrolidin-4-yl,1-(6-chloropyrimidin-4-yl)piperidin-4-yl,5-(4-chlorophenyl)thiophen-2-yl, 2-(4-chlorophenyl)thiazol-4-yl,3-(4-chlorophenyl)-1H-pyrrol-2-yl, 4-(4-pyrimidinyl)phenyl and4-(4-imidazolyl)phenyl groups.

<On Group Q³>

The group Q³ represents the following group:

wherein Q⁵ means an alkylene group having 1 to 8 carbon atoms, analkenylene group having 2 to 8 carbon atoms, or a group—(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n are independently ofeach other 0 or an integer of 1-3, and A means an oxygen atom, nitrogenatom, sulfur atom, —SO—, —SO₂—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH—or —SO₂—NH—, numerals 1 and 2 indicate positions, and R³ and R⁴ aresubstituents on carbon atom(s), nitrogen atom(s) or sulfur atom(s) of aring comprising Q⁵ and are independently of each other a hydrogen atom,hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom,halogenoalkyl group, cyano group, cyanoalkyl group, amino group,aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group,acyl group, acylalkyl group, acylamino group which may be substituted,alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group,alkoxycarbonylalkylamino group, carboxyalkylamino group,alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoylgroup, N-alkylcarbamoyl group which may have a substituent on the alkylgroup, N,N-dialkylcarbamoyl group which may have a substituent on thealkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group,N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group,N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group,N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberedheterocyclic carbonyl group which may be substituted, carbamoylalkylgroup, N-alkylcarbamoylalkyl group which may have a substituent on thealkyl group(s), N,N-dialkylcarbamoylalkyl group which may have asubstituent on the alkyl group(s), carbamoyloxyalkyl group,N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3-to 6-membered heterocyclic carbonylalkyl group which may be substituted,3- to 6-membered heterocyclic carbonyloxyalkyl group which may besubstituted, aryl group, aralkyl group, heteroaryl group,heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylaminogroup, alkylsultonylaminoalkyl group, arylsulfonylaminoalkyl group,alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group,alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkylgroup, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxygroup, acyloxy group, acyloxyalkyl group, arylsulfonyl group,alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacylgroup, alkoxyacyl group, halogenoacyl group, carboxyacyl group,aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group,hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-memberedheterocyclic sulfonyl group which may be substituted, N-alkylaminoacylgroup, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group whichmay have a substituent on the alkyl group(s),N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent onthe alkyl group(s) or alkylsulfonylacyl group, or R³ and R⁴, togetherwith each other, denote an alkylene group having 1 to 5 carbon atoms,alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having1 to 5 carbon atoms or carbonyldioxy group.

The following group will be described in detail.

wherein Q⁵, R³ and R⁴ have the same meanings as defined above, andnumerals 1 and 2 indicate positions.

A portion of the cyclic structure having the group Q⁵ is a 3- to10-membered divalent cyclic hydrocarbon group which may have a doublebond, or a 5- to 12-membered divalent heterocyclic group containing 1 or2 hetero atoms, preferably a 3- to 8-membered divalent cyclichydrocarbon group or a 5- to 8-membered divalent heterocyclic group,more preferably a 5- to 7-membered divalent cyclic hydrocarbon group ora 5- to 7-membered divalent heterocyclic group. Among others, a group inwhich Q⁵ is an alkylene group having 3 to 6 carbon atoms or a group—(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n are independently ofeach other 0 or 1, and A has the same meaning as defined above, ispreferred. In particular, a group in which Q⁵ is an alkylene grouphaving 4 carbon atoms is preferred.

This cyclic hydrocarbon group or heterocyclic group may have both cisand trans structures in the relation between position 1 and position 2.However, the trans-form is preferred in the case of the 5-membered ring,while both cis-form and trans-form are preferred in the 6- or 7-memberedring.

The substituents R³ and R⁴ will now be described in detail. The halogenatom means a fluorine, chlorine, bromine or iodine atom. Examples of thealkyl group include linear, branched or cyclic C₁-C₆ alkyl groups (forexample, methyl group, cyclopropyl group, isobutyl group and the like).Examples of the halogenoalkyl group include the 1 to 3halogen-substituted alkyl groups (for example, chloromethyl group,1-bromoethyl group, trifluoromethyl group and the like). Examples of thecyanoalkyl group include the C₁-C₆ alkyl groups substituted with a cyanogroup (for example, cyanomethyl group, 1-cyanoethyl group and the like).Examples of the alkenyl group include linear or branched alkenyl groupshaving 2 to 6 carbon atoms and a double bond (for example, vinyl group,allyl group and the like). Examples of the alkynyl group include linearor branched alkynyl groups having 2 to 6 carbon atoms and a triple bond(for example, ethynyl group, propynyl group and the like). Examples ofthe acyl group include C₁-C₆ alkanoyl groups (for example, formyl group,acetyl group and the like), C₇-C₁₅ aroyl groups such as a benzoyl groupand a naphthoyl group, and arylalkanoyl groups that are the C₁-C₆alkanoyl groups substituted with a C₆-C₁₄ aryl group (for example,phenacetyl group and the like). Examples of the acylalkyl group includethe C₁-C₆ alkyl groups substituted with the acyl group (for example,acethylmethyl group and the like). Examples of the alkoxy group includelinear, branched or cyclic C₁-C₆ alkoxy groups (for example, methoxygroup, cyclopropoxy group, an isopropoxy group and the like). Examplesof the alkoxyalkyl group include the C₁-C₆ alkyl groups substituted withthe C₁-C₆ alkoxy group (for example, methoxymethyl group, ethoxymethylgroup and the like). Examples of the hydroxyalkyl group include theC₁-C₆ alkyl groups substituted with a hydroxyl group (for example,hydroxymethyl group, 1-hydroxyethyl group and the like). Examples of thecarboxyalkyl group include the C₁-C₆ alkyl groups substituted with acarboxyl group (for example, carboxymethyl group, 1-carboxyethyl groupand the like). Examples of the alkoxycarbonyl group include groupscomposed of the C₁-C₆ alkoxy group and a carbonyl group (for example,methoxycarbonyl group, ethoxycarbonyl group and the like). Examples ofthe alkoxycarbonylalkyl group include the C₁-C₆ alkyl groups substitutedwith the C₁-C₆ alkoxycarbonyl group (for example, methoxycarbonylethylgroup, ethoxycarbonylethyl group and the like). Examples of thecarbamoylalkyl group include the C₁-C₆ alkyl groups substituted acarbamoyl group (for example, carbamoylmethyl group, carbamoylethylgroup and the like).

Examples of the heteroaryl group include the same heteroaryl groups asdescribed in the description of Q⁴ in the general formula (1). Examplesof the heteroarylalkyl group include the C₁-C₆ alkyl groups substitutedwith the heteroaryl group (for example, thienylmethyl group,pyridylethyl group and the like). Examples of the aryl group includearyl groups having 6 to 14 carbon atoms, such as phenyl group andnaphthyl group. The aryl groups may have 1 to 3 substituents selectedfrom the C₁-C₆ alkyl groups, the C₁-C₆ alkanoyl groups, a hydroxylgroup, a nitro group, a cyano group, halogen atoms, the C₂-C₆ alkenylgroups, the C₂-C₆ alkynyl groups, the C₁-C₆ halogenoalkyl groups, theC₁-C₆ alkoxy groups, a carboxy group, a carbamoyl group, the C₁-C₆alkoxycarbonyl groups and the like. Examples of the aralkyl groupinclude the C₁-C₆ alkyl groups substituted with the C₆-C₁₄ aryl groups(for example, benzyl group, phenethyl group and the like). Incidentally,in the above description, no particular limitation is imposed on thesubstituting position. Examples of the acylamino group which may besubstituted include the amino groups substituted with the C₁-C₆ acylgroup (for example, formylamino group, acetylamino group and the like)and besides acyl groups having 1 to several substituents selected fromhalogen atoms, a hydroxyl group, C₁-C₆ alkoxy groups, a amino group,N—C₁-C₆ alkylamino groups, N,N-di-C₁-C₆ alkylamino groups, a carboxylgroup, C₂-C₆ alkoxycarbonyl groups and the like (for example,2-methoxyacetylamino group, 3-aminopropionylamino group and the like).Examples of the acylaminoalkyl group include the C₁-C₆ alkyl groupssubstituted with the C₁-C₆ acylamino group (for example,formylaminomethyl group, acetylaminomethyl group and the like). Examplesof the aminoalkyl group include the C₁-C₆alkyl groups substituted withan amino group (for example, aminomethyl group, 1-aminoethyl group andthe like). Examples of the N-alkylaminoalkyl group include theamino-C₁-C₆ alkyl groups substituted with the C₁-C₆alkyl group on thenitrogen atom (for example, N-methylaminomethyl group,N-methylaminoethyl group and the like). Examples ofN,N-dialkylaminoalkyl group include the amino-C₁-C₆ alkyl groupsrespectively substituted with two C₁-C₆alkyl groups on the nitrogen atom(for example, N,N-dimethylaminomethyl group, N-ethyl-N-methylaminoethylgroup and the like). Examples of the N-alkenylcarbamoyl group includecarbamoyl groups substituted with a linear or branched C₂-C₆ alkenylgroup (for example, allylcarbamoyl group and the like). Examples of theN-alkenylcarbamoylalkyl group include the C₁-C₆ alkyl groups substitutedwith the N—C₂-C₆ alkenylcarbamoyl group (for example,allylcarbamoylethyl group and the like). Examples of theN-alkenyl-N-alkylcarbamoyl group include the N—C₂-C₆ alkenylcarbamoylgroups substituted with a linear or branched C₁-C₆ alkyl group on thenitrogen atom (for example, N-allyl-N-methylcarbamoyl group and thelike). Examples of the N-alkenyl-N-alkylcarbamoylalkyl group include theN—C₂-C₆ alkenylcarbamoylalkyl groups substituted with a linear orbranched C₁-C₆ alkyl group on the nitrogen atom (for example,N-allyl-N-methylcarbamoylmethyl group and the like). Example of theN-alkoxycarbamoyl group include carbamoyl groups substituted with alinear or branched C₁-C₆ alkoxy group (for example, methoxycarbamoylgroup and the like). Examples of the N-alkoxycarbamoylalkyl groupinclude linear or branched C₁-C₆ alkyl groups substituted with theN—C₁-C₆ alkoxycarbamoyl group (for example, methoxycarbamoylmethyl groupand the like). Examples of the N-alkyl-N-alkoxycarbamoyl group includecarbamoyl groups substituted with linear or branched C₁-C₆ alkoxy groupand C₁-C₆ alkyl group (for example, N-ethyl-N-methoxycarbamoyl group andthe like). Examples of the N-alkyl-N-alkoxycarbamoylalkyl group includelinear or branched C₁-C₆ alkyl groups substituted with the N—C₁-C₆alkyl-N—C₁-C₆ alkoxycarbamoyl group (for example,N-ethyl-N-methoxycarbamoylmethyl group and the like). Examples of thecarbazoyl group which may be substituted by 1 to 3 alkyl groups includea carbazoyl group, and besides carbazoyl groups substituted with 1 to 3linear or branched C₁-C₆ alkyl groups (for example, 1-methylcarbazoylgroup, 1,2-dimethylcarbazoyl group and the like). Examples of thealkylsulfonyl group include linear, branched or cyclic C₁-C₆alkylsulfonyl groups (for example, methanesulfonyl group and the like).Examples of the alkylsulfonylalkyl group include linear or branchedC₁-C₆ alkyl groups substituted with the C₁-C₆ alkylsulfonyl group (forexample, methanesulfonylmethyl group and the like). Examples of thealkoxyimino group include C₁-C₆ alkoxyimino groups (for example,methoxyimino group, ethoxyimino group and the like). Examples of thealkoxycarbonylalkylamino group include amino groups substituted with theC₁-C₆ alkoxycarbonylalkyl group (for example, methoxycarbonylmethylaminogroup, ethoxycarbonylpropylamino group and the like). Examples of thecarboxyalkylamino group include amino groups substituted with thecarboxy-C₁-C₆ alkyl group (for example, carboxymethylamino group,carboxyethylamino group and the like). Examples of thealkoxycarbonylamino group include amino groups substituted with theC₁-C₆ alkoxycarbonyl group (for example, methoxycarbonylamino group,tert-butoxycarbonylamino group and the like). Examples of thealkoxycarbonylaminoalkyl group include the alkyl groups substituted withthe C₁-C₆ alkoxycarbonylamino group (for example,methoxycarbonylaminomethyl group, tert-butoxycarbonylaminoethyl groupand the like). The N-alkylcarbamoyl group which may have a substituenton the alkyl group means a carbamoyl group substituted with a linear,branched or cyclic C₁-C₆ alkyl group which may be substituted with ahydroxyl group, amino group, N—C₁-C₆ alkylamino group, amidino group,halogen atom, carboxyl group, cyano group, carbamoyl group, C₁-C₆ alkoxygroup, C₁-C₆ alkanoyl group, C₁-C₆ alkanoylamino group, C₁-C₆alkylsulfonylamino group or the like, and examples thereof includeN-methylcarbamoyl group, N-ethylcarbamoyl group, N-isopropylcarbamoylgroup, N-cyclopropylcarbamoyl group, N-(2-hydroxyethyl)carbamoyl group,N-(2-fluoroethyl)carbamoyl group, N-(2-cyanoethyl)carbamoyl group,N-(2-methoxyethyl)carbamoyl group, N-carboxymethylcarbamoyl group,N-(2-aminoethyl)carbamoyl group, N-(2-amidinoethyl)carbamoyl group andthe like. Examples of the N,N-dialkylcarbamoyl group which may have asubstituent on the alkyl(s) group means a carbamoyl group substitutedwith 2 linear, branched or cyclic C₁-C₆ alkyl groups which may besubstituted with a hydroxyl group, amino group, N—C₁-C₆ alkylaminogroup, amidino group, halogen atom, carboxyl group, cyano group,carbamoyl group, C₁-C₆ alkoxy group, C₁-C₆ alkanoyl group, C₁-C₆alkanoylamino group, C₁-C₆ alkylsulfonylamino group or the like, andexamples thereof include N,N-dimethylcarbamoyl group,N,N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group,N-isopropyl-N-methylcarbamoyl group,N-(2-hydroxyethyl)-N-methylcarbamoyl group,N,N-bis(2-hydroxyethyl)-carbamoyl group, N,N-bis(2-fluoroethyl)carbamoylgroup, N-(2-cyanoethyl)-N-methylcarbamoyl group,N-(2-methoxyethyl)-N-methylcarbamoyl group,N-carboxymethyl-N-methylcarbamoyl group, N,N-bis(2-aminoethyl)carbamoylgroup and the like. Examples of the N-alkylcarbamoylalkyl group whichmay have a substituent on the alkyl group(s) include linear or branchedC₁-C₆ alkyl groups substituted with the N-alkylcarbamoyl group which mayhave a substituent on the C₁-C₆ alkyl group (for example,N-methylcarbamoylmethyl group, N-(2-hydroxyethyl)carbamoylmethyl groupand the like). Examples of the N,N-dialkylcarbamoylalkyl group which mayhave a substituent on the alkyl group(s) include linear or branchedC₁-C₆ alkyl groups substituted with the N,N-dialkylcarbamoyl group whichmay have a substituent on the C₁-C₆ alkyl group(s) (for example,N,N-dimethylcarbamoylmethyl group,N-(2-hydroxyethyl)-N-methylcarbamoylmethyl group and the like). The 3-to 6-membered heterocyclic carbonyl group which may be substituted is agroup composed of a saturated or unsaturated heterocyclic ring and acarbonyl group. The heterocyclic ring means a 3- to 6-memberedheterocyclic ring which may containing 1 to 3 hetero atoms (nitrogenatom, oxygen atom, sulfur atom, etc.). The heterocyclic ring may have asubstituent such as a hydroxy group, halogen atom, amino group, C₁-C₆alkyl group or the like. As specific examples thereof, may be mentionedan aziridinylcarbonyl group, azetidinylcarbonyl group,3-hydroxyazetidinylcarbonyl group, 3-methoxyazetidinylcarbonyl group,pyrrolidinylcarbonyl group, 3-hydroxypyrrolidinylcarbonyl group,3-fluoropyrrolidinylcarbonyl group, piperidinylcarbonyl group,piperazinylcarbonyl group, morpholinylcarbonyl group,tetrahydropyranylcarbonyl group, pyridylcarbonyl group, furoyl group andthiophenecarbonyl group. Examples of the 3- to 6-membered heterocycliccarbonylalkyl group which may be substituted include the C₁-C₆ alkylgroups substituted with the 3- to 6-membered heterocyclic carbonyl groupwhich may be substituted (for example, azetidinylcarbonylmethyl group,pyrrolidinylcarbonylethyl group and the like). Examples of the 3- to6-membered heterocyclic carbonyloxyalkyl group which may be substitutedinclude the C₁-C₆ alkyl groups substituted with the 3- to 6-memberedheterocyclic carbonyloxy group which is composed of the 3- to 6-memberedheterocyclic carbonyl group and an oxygen atom (for example,piperidinylcarbonyloxyethyl group, morpholinylcarbonyloxymethyl groupand the like).

Examples of the carbamoyloxyalkyl group include the C₁-C₆ alkyl groupssubstituted with a carbamoyloxy group which is composed of a carbamoylgroup and an oxygen atom (for example, carbamoyloxymethyl group,carbamoyloxyethyl group and the like). Examples of theN-alkylcarbamoyloxyalkyl group include the C₁-C₆ alkyl groupssubstituted with the N-alkylcarbamoyloxy group which is composed of theN-alkylcarbamoyl group, which may have a substituent on the C₁-C₆ alkylgroup, and an oxygen atom (for example, N-methylcarbamoyloxymethylgroup, N-methylcarbamoyloxyethyl group and the like). Examples of theN,N-dialkylcarbamoyloxyalkyl group include the C₁-C₆ alkyl groupssubstituted with the N,N-dialkylcarbamoyloxy group which is composed ofthe N,N-dialkylcarbamoyl group, which may have a substituent on thealkyl group(s), and an oxygen atom (for example,N,N-dimethylcarbamoyl-oxymethyl group, N-ethyl-N-methylcarbamoyloxyethylgroup and the like). Examples of the alkylsulfonylamino group includeamino groups substituted with an alkylsulfonyl group having the C₁-C₆alkyl group (for example, methylsulfonylamino group,isopropylsulfonylamino group and the like). Examples of thearylsulfonylamino group include amino groups substituted with anarylsulfonyl group having the aryl group (for example,phenylsulfonylamino group, naphthylsulfonylamino group and the like).Examples of the alkylsulfonylaminoalkyl group include the C₁-C₆ alkylgroups substituted with the C₁-C₆ alkylsulfonylamino group (for example,methylsulfonylaminomethyl group, methylsulfonylaminoethyl group and thelike). Examples of the arylsulfonylaminoalkyl group include the C₁-C₆alkyl groups substituted with the arylsulfonylamino group (for example,phenylsulfonylaminomethyl group, naphthylsulfonylaminoethyl group andthe like). Examples of the alkylsulfonylaminocarbonyl group includegroups composed of the C₁-C₆ alkylsulfonylamino group and a carbonylgroup (for example, methylsulfonylaminocarbonyl group,isopropylsulfonylaminocarbonyl group and the like). Examples of thearylsulfonylaminocarbonyl group include groups composed of thearylsulfonylamino group and a carbonyl group (for example,phenylsulfonylaminocarbonyl group, naphthylsulfonylaminocarbonyl groupand the like). Examples of the alkylsulfonylaminocarbonylalkyl groupinclude the C₁-C₆ alkyl groups substituted with the C₁-C₆alkylsulfonylaminocarbonyl group (for example,methylsulfonylaminocarbonylmethyl group,isopropylsulfonylaminocarbonylmethyl group and the like). Examples ofthe arylsulfonylaminocarbonylalkyl group include the C₁-C₆ alkyl groupssubstituted with the arylsulfonylaminocarbonyl group (for example,phenylsulfonylaminocarbonylmethyl group,naphthylsulfonylaminocarbonylmethyl group and the like). The acyloxygroup means a group composed of the acyl group and an oxygen atom (forexample, formyloxy group, acetyloxy group and the like). Examples of theacyloxyalkyl group include the C₁-C₆ alkyl groups substituted with theacyloxy group (for example, formyloxymethyl group, acetyloxymethyl groupand the like). Examples of the aralkyloxy group include the C₁-C₆ alkoxygroups substituted with the aryl group (for example, benzyloxy group,naphthylmethoxy group and the like). Examples of the carboxyalkyloxygroup include the alkoxy groups substituted with a carboxyl group (forexample, carboxymethoxy group, carboxyethoxy group and the like).

Examples of the arylsulfonyl group include C₆-C₁₄ arylsulfonyl groups(for example, phenylsulfonyl group, naphthylsulfonyl group and thelike). Examples of the alkoxycarbonylalkylsulfonyl group include groupscomposed of the C₁-C₆ alkoxycarbonylalkyl group and a sulfonyl group(for example, methoxycarbonylethylsulfonyl group,ethoxycarbonylethylsulfonyl group and the like). Examples of thecarboxyalkylsulfonyl group include groups composed of the carboxyalkylgroup and a sulfonyl group (for example, carboxymethylsulfonyl group,carboxyethylsulfonyl group and the like). Examples of thealkoxycarbonylacyl group include groups composed of thealkoxycarbonylalkyl group and a carbonyl group (for example,methoxycarbonylmethylcarbonyl group, ethoxycarbonylmethylcarbonyl groupand the like). Examples of the alkoxyalkyloxycarbonyl group include thealkoxycarbonyl groups substituted with the C₁-C₆ alkoxy group (forexamples, methoxymethyloxycarbonyl group, methoxyethyloxycarbonyl groupand the like). Examples of the hydroxyacyl group include the acyl groups(including C₁-C₆ alkanoyl and aroyl) substituted with a hydroxyl group(for example, glycoloyl group, lactoyl group, benziloyl group and thelike). Examples of the alkoxyacyl group include the acyl groupssubstituted with the C₁-C₆ alkoxy group (for example, methoxyacetylgroup, ethoxyacetyl group and the like). Examples of the halogenoacylgroup include groups composed of the halogenoalkyl group and a carbonylgroup (for example, chloromethylcarbonyl group, trifluoromethylcarbonylgroup and the like). Examples of the carboxyacyl group include the acylgroups substituted with a carboxyl group (for example, carboxyacetylgroup, 2-carboxypropionyl group and the like). Examples of the aminoacylgroup include the acyl groups (including C₁-C₆ alkanoyl and aroyl)substituted with an amino group (for example, aminomethylcarbonyl group,1-aminoethylcarbonyl group and the like). Examples of the acyloxyacylgroup include groups composed of the acyloxyalkyl and a carbonyl group(for example, formyloxymethylcarbonyl group, acetyloxymethylcarbonylgroup and the like). Examples of the acyloxyalkylsulfonyl group includegroups composed of the acyloxyalkyl and a sulfonyl group (for example,formyloxymethylsulfonyl group, acetyloxymethylsulfonyl group and thelike). Examples of the hydroxyalkylsulfonyl group include groupscomposed of the C₁-C₆ hydroxyalkyl group and a sulfonyl group (forexample, hydroxymethylsulfonyl group, 1-hydroxyethylsulfonyl group andthe like). Examples of the alkoxyalkylsulfonyl group include the groupscomposed of C₁-C₆ alkoxyalkyl group and a sulfonyl group (for example,methoxymethylsulfonyl group, ethoxyethylsulfonyl group and the like).Examples of the 3- to 6-membered heterocyclic sulfonyl group which maybe substituted include groups composed of the 3- to 6-memberedheterocyclic group which may be substituted and a sulfonyl group (forexample, aziridinylsulfonyl group, azetidinylsulfonyl group,pyrrolidinylsulfonyl group, piperidylsulfonyl group, piperazinylsulfonylgroup, morpholinylsulfonyl group, tetrahydropyranylsulfonyl group andthe like). Examples of the N-alkylaminoacyl group include the aminoacylgroups substituted with the C₁-C₆ alkyl group on the nitrogen atom (forexample, N-methylaminoacetyl group, N-ethylaminoacetyl group and thelike). Examples of the N,N-dialkylaminoacyl group include the aminoacylgroups substituted with the two C₁-C₆ alkyl groups on the nitrogen atoms(for example, N,N-dimethylaminoacetyl group, N-ethyl-N-methylaminoacetylgroup and the like). Examples of the N,N-dialkylcarbamoylacyl groupwhich may have a substituent on the alkyl group(s) include the acylgroups substituted with the N,N-dialkylcarbamoyl group which may have asubstituent on the C₁-C₆ alkyl group(s) (for example,N,N-dimethylcarbamoylacetyl group, N,N-diethylcarbamoylacyl group,N-ethyl-N-methylcarbamoylacetyl group and the like). Examples of theN,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent onthe alkyl group(s) include groups composed of the N,N-dialkylcarbamoylgroup which may have a substituent on the C₁-C₆ alkyl group(s) and asulfonyl group (for example, N,N-dimethylcarbamoylmethylsulfonyl group,N-(2-hydroxyethyl)-N-methylcarbamoylmethyl-sulfonyl group and the like).Examples of the alkylsulfonylacyl group include the acyl groupssubstituted with the alkylsulfonyl group having the C₁-C₆ alkyl group(for example, methylsulfonylacetyl group, isopropylsulfonylacetyl groupand the like).

The alkylene group means a linear or branched alkylene group having 1 to5 carbon atoms, and examples thereof include methylene group, ethylenegroup, propylene group and the like. The alkenylene group is analkenylene group having 2 to 5 carbon atoms and a double bond, andexamples thereof include vinylene group, propenylene group and the like.Examples of the alkylenedioxy group include those having 1 to 5 carbonatoms, such as methylenedioxy group, ethylenedioxy group andpropylenedioxy group. The carbonyldioxy group is a group represented by—O—C(═O)—O—. Incidentally, no particular limitation is imposed on thesubstituting position in the above description.

Among these substituents represented by R³ and R⁴, the hydrogen atom,hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom,halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group,aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group,acyl group, acylalkyl group, acylamino group which may be substituted,acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkylgroup, carboxyl group, carboxyalkyl group, alkoxycarbonyl group,alkoxycarbonylalkyl group, alkoxycarbonylamino group,alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl groupwhich may have a substituent on the alkyl group, N,N-dialkylcarbamoylgroup which may have a substituent on the alkyl group(s),N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group,N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group,N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group,N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberedheterocyclic carbonyl group which may be substituted, 3- to 6-memberedheterocyclic carbonyloxyalkyl group which may be substituted,carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkylgroup, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl groupwhich may have a substituent on the alkyl group(s),N,N-dialkylcarbamoylalkyl group which may have a substituent on thealkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group,oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group,alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonylgroup, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacylgroup, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group,N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group,alkylsulfonylacyl group and the like are preferred. The alkylene group,alkenylene group, alkylenedioxy group carbonyldioxy group and the likewhich are formed by R³ and R⁴ together with each other are alsopreferred.

It is preferred that R³ be a hydrogen atom, and R⁴ be one of thesubstituents mentioned above as preferable groups. In this case,examples of a group more preferred as R⁴ include the hydrogen atom,hydroxyl group, alkyl group, halogen atom, hydroxyimino group,N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group,acylamino group which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylaminogroup, carbamoyl group, N-alkylcarbamoyl group which may have asubstituent on the alkyl group, N,N-dialkylcarbamoyl group which mayhave a substituent on the alkyl group(s), N-alkenylcarbamoyl group,N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group,N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group,N-alkyl-N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberedheterocyclic carbonyl group which may be substituted, 3- to 6-memberedheterocyclic carbonyloxyalkyl group which may be substituted,carbamoylalkyl group, N,N-dialkylcarbamoyloxyalkyl group,N-alkylcarbamoylalkyl group which may have a substituent on the alkylgroup(s), N,N-dialkylcarbamoylalkyl group which may have a substituenton the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkylgroup, acyloxy group, arylsulfonyl group, alkoxycarbonylalkylsulfonylgroup, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacylgroup, alkoxyalkyloxycarbonyl group, halogenoacyl group,N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group,alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacylgroup, N,N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl groupand the like.

Of these, as examples of R⁴, are particularly preferred the hydrogenatom, hydroxyl group, alkyl group, N,N-dialkylaminoalkyl group,acylamino group which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, alkoxycarbonyl group,alkoxycarbonylamino group, carbamoyl group, N-alkylcarbamoyl group whichmay have a substituent on the alkyl group, N,N-dialkylcarbamoyl groupwhich may have a substituent on the alkyl group(s), N-alkenylcarbamoylgroup, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group,N-alkenyl-N-alkylcarbamoylalkyl group, N-alkyl-N-alkoxycarbamoyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberedheterocyclic carbonyl group which may be substituted,N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group whichmay have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkylgroup which may have a substituent on the alkyl group(s),alkylsulfonylamino group, alkylsulfonylaminoalkyl group, acyloxy group,acyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group,N,N-dialkylaminoacyl group, hydroxyacyl group, alkoxyacyl group and thelike.

As specific preferable examples of R³ and R⁴, may be mentioned ahydrogen atom, hydroxyl group, methyl group, ethyl group, isopropylgroup, N,N-dimethylaminomethyl group, N,N-dimethylaminoethyl group,N,N-diethylaminomethyl group, acetylamino group, methoxyacetylaminogroup, acetylaminomethyl group, acetylaminoethyl group, methoxy group,ethoxy group, methoxymethyl group, methoxyethyl group, hydroxymethylgroup, 2-hydroxyethyl group, 1-hydroxy-1-methylethyl group,methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonylamino group,ethoxycarbonylamino group, N-allylcarbamoyl group,N-allylcarbamoylmethyl group, N-allyl-N-methylcarbamoyl group,N-allyl-N-methylcarbamoylmethyl group, N-methoxy-N-methylcarbamoylgroup, N,N-dimethylcarbazoyl group, N,N,N′-trimethylcarbazoyl group,methanesulfonyl group, methanesulfonylmethyl group, ethanesulfonylmethylgroup, N-methylcarbamoyl group, N-ethylcarbamoyl group,N-propylcarbamoyl group, N-isopropylcarbamoyl group,N-tert-butylcarbamoyl group, N-cyclopropylcarbamoyl group,N-cyclopropylmethylcarbamoyl group,N-(1-ethoxycarbonylcyclopropyl)carbamoyl group,N-(2-hydroxyethyl)carbamoyl group, N-(2-fluoroethyl)carbamoyl group,N-(2-methoxyethyl)carbamoyl group, N-(carboxymethyl)-carbamoyl group,N-(2-aminoethyl)carbamoyl group, N-(2-amidinoethyl)carbamoyl group,N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group,N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group,N-methyl-N-propylcarbamoyl group, N-(2-hydroxyethyl)-N-methylcarbamoylgroup, N-(2-fluoroethyl)-N-methylcarbamoyl group,N,N-bis(2-hydroxyethyl)carbamoyl group, N,N-bis(2-fluoroethyl)carbamoylgroup, N-(2-methoxyethyl)-N-methylcarbamoyl group,N-carboxymethyl-N-methylcarbamoyl group, N,N-bis(2-aminoethyl)carbamoylgroup, azetidinocarbonyl group, 3-methoxyazetidinocarbonyl group,3-hydroxyazetidinocarbonyl group, pyrrolidinocarbonyl group,3-hydroxypyrrolidinocarbonyl group, 3-fluoropyrrolidinocarbonyl group,3,4-dimethoxypyrrolidinocarbonyl group, piperidinocarbonyl group,piperazinocarbonyl group, morpholinocarbonyl group,(tetrahydropyran-4-yl)carbonyl group, benzoyl group, pyridylcarbonylgroup, N-methylcarbamoylmethyl group, N-methylcarbamoylethyl group,N-ethylcarbamoylmethyl group, N-(2-fluoroethyl)carbamoylmethyl group,N-(2-methoxyethyl)carbamoylmethyl group, N,N-dimethylcarbamoylmethylgroup, N,N-dimethylcarbamoylethyl group,N-(2-fluoroethyl)-N-methylcarbamoylmethyl group,N-(2-methoxyethyl)-N-methylcarbamoylmethyl group,N,N-dimethylcarbamoyloxymethyl group,2-(N-ethyl-N-methylcarbamoyloxy)ethyl group, methylsulfonylamino group,ethylsulfonylamino group, methylsulfonylaminomethyl group,methylsulfonylaminoethyl group, acetyl group, propionyl group,isobutyryl group, 2-methoxyethoxycarbonyl group, trifluoroacetyl group,N,N-dimethylaminoacetyl group, N-ethyl-N-methylaminoacetyl group,hydroxyacetyl group, 1,1-dimethyl-2-hydroxyethylcarbonyl group,methoxyacetyl group, 1,1-dimethyl-2-methoxyethylcarbonyl group and thelike.

As described above, it is preferred that R³ be a hydrogen atom, and R⁴be one of these specified substituents, preferably, anN,N-dialkylcarbamoyl group which may have a substituent on the alkylgroup(s), particularly preferably, an N,N-dimethylcarbamoyl group.However, R³ and R⁴ are not limited to these specific substituents atall.

<On Group T⁰>

The group T⁰ represents a carbonyl group or thiocarbonyl group, with thecarbonyl group being preferred.

<On Group T¹>

The group T¹ represents a carbonyl group, sulfonyl group, group—C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group—C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)—, in which R′ means ahydrogen atom, hydroxyl group, alkyl group or alkoxy group, group—C(═O)-A¹-N(R″)—, in which A¹ means an alkylene group having 1 to 5carbon atoms, which may be substituted, and R″ means a hydrogen atom,hydroxyl group, alkyl group or alkoxy group, group —C(═O)—NH—, group—C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A²-C(═O)—, in which A²means a single bond or alkylene group having 1 to 5 carbon atoms, group—C(═O)-A³-C(═O)—NH—, in which A³ means an alkylene group having 1 to 5carbon atoms, group —C(═O)—C(═NOR^(a))—N(R^(b))—, group—C(═S)—C(═NOR^(a))—N(R^(b))—, in which R^(a) means a hydrogen atom,alkyl group or alkanoyl group, and R^(b) means a hydrogen atom, hydroxylgroup, alkyl group or alkoxy group, group —C(═O)—N═N—, group—C(═S)—N═N—, or thiocarbonyl group.

In the above group, the alkylene group having 1 to 5 carbon atoms in A¹,A² and A³ means a linear, branched or cyclic alkylene group having 1 to5 carbon atoms, and examples thereof include methylene, ethylene,propylene, cyclopropylene, 1,3-cyclopentylene groups and the like. Thealkyl group in R′, R″, R^(a) and R^(b) means a linear, branched orcyclic alkyl group having 1 to 6 carbon atoms, and examples thereofinclude methyl, ethyl groups and the like. The alkoxy group means alinear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, andexamples thereof include methoxy, ethoxy groups and the like.

In R^(a), the alkanoyl group means a group composed of a linear,branched or cyclic alkyl group having 1 to 6 carbon atoms and a carbonylgroup, and examples thereof include acetyl, propionyl groups and thelike.

As T¹, is preferred a carbonyl group, group —C(═O)—C(═O)—N(R′)—, group—C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group—C(═S)—C(═S)—N(R′)— and group —C(═O)—CH₂—N(R′)—, with a carbonyl group,group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group—C(═O)—C(═S)—N(R′)— and group —C(═S)—C(═S)—N(R′)— being particularlypreferred.

<On Group R¹ and Group R²>

R¹ and R² are, independently of each other, a hydrogen atom, hydroxylgroup, alkyl group or alkoxy group, preferably a hydrogen atom or alkylgroup, more preferably a hydrogen atom.

In R¹ and R², the alkyl group means a linear, branched or cyclic alkylgroup having 1 to 6 carbon atoms, and examples thereof include methyl,ethyl groups and the like. The alkoxy group means a linear, branched orcyclic alkoxy group having 1 to 6 carbon atoms, and examples thereofinclude methoxy, ethoxy groups and the like. R¹ and R² are preferably,independently of each other, a hydrogen atom or alkyl group, morepreferably both hydrogen atoms.

When T¹ is a carbonyl or sulfonyl group, and Q⁵ in the group Q³ is analkylene group having 1 to 8 carbon atoms or an alkenylene group having2 to 8 carbon atoms, Q⁴ is preferably a group (b), (f), (g), (h), (i),(j), (k) and (l) of the above-described 12 groups, with the provise thatN in the group (f) indicates that 2 carbon atoms of the ring substitutedby R¹⁹ have been substituted by a nitrogen atom.

When T¹ is a carbonyl or sulfonyl group, and Q⁵ in the group Q³ is analkylene group having 1 to 8 carbon atoms or an alkenylene group having2 to 8 carbon atoms, the substituent on the group Q⁵ is preferably anN-alkylcarbamoyl or N,N-dialkylcarbamoyl group.

When T¹ is a group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group—C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—, and Q⁵ in the group Q³is an alkylene group having 1 to 8 carbon atoms or an alkenylene grouphaving 2 to 8 carbon atoms, Q⁴ is preferably a group (i), (j) or (k) ofthe above-described 12 groups.

When T¹ is a group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group—C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—, and Q⁵ in the group Q³is an alkylene group having 1 to 8 carbon atoms or an alkenylene grouphaving 2 to 8 carbon atoms, the substituent on the group Q⁵ ispreferably an N-alkylcarbamoyl or N,N-dialkylcarbamoyl group.

A feature of the compounds of the present invention represented by thegeneral formula (1), the salts thereof, the solvates thereof, or theN-oxides thereof resides in a combination of the group T¹ and the groupQ³. The combination is roughly divided into the following 2 cases (I)and (II):

(I) A case where T¹ is a carbonyl, sulfonyl or thiocarbonyl group, andQ³ is the following group:

wherein Q⁵ means a group —(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m andn are independently of each other 0 or an integer of 1-3, and A means anoxygen atom, nitrogen atom, sulfur atom, —SO—, —SO₂—, —NH—, —O—NH—,—NH—NH—, —S—NH—, —SO—NH— or —SO₂—NH—; and(II) a case where T¹ is a group —C(═O)—C(═O)—N(R′)—, group—C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group—C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group,alkyl group or alkoxy group, group —C(═O)-A¹-N(R″)—, in which A¹ meansan alkylene group having 1 to 5 carbon atoms, which may be substituted,and R″ means a hydrogen atom, hydroxyl group, alkyl group or alkoxygroup, group —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group—C(═O)-A²-C(═O)—, in which A² means a single bond or alkylene grouphaving 1 to 5 carbon atoms, group —C(═O)-A³—C(═O)—NH—, in which A³ meansan alkylene group having 1 to 5 carbon atoms or thiocarbonyl group, andQ³ is the following group:

wherein Q⁵ means an alkylene group having 1 to 8 carbon atoms, analkenylene group having 2 to 8 carbon atoms or a group—(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n are independently ofeach other 0 or an integer of 1-3, and A means an oxygen atom, nitrogenatom, sulfur atom, —SO—, —SO₂—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH—or —SO₂—NH—.

In the cases (I) and (II), the following (i) and (ii) are mentioned aspreferred examples, respectively.

(i) An example where the group R¹ and the group R² are, independently ofeach other, a hydrogen atom or alkyl group, the group Q¹ is a saturatedor unsaturated, bicyclic or tricyclic fused hydrocarbon group which maybe substituted, or a saturated or unsaturated, bicyclic or tricyclicfused heterocyclic group which may be substituted, the group Q² is asingle bond, the group Q⁵ in the group Q³ is a group—(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n are independently ofeach other 0 or 1, and A has the same meaning as defined above, thegroup Q⁴ is selected from 9 groups (a) to (h) and (1) of theabove-described 12 groups, the group T⁰ is a carbonyl group orthiocarbonyl group, and the group T¹ is a carbonyl group or sulfonylgroup; and

(ii) An example where in the generally formula (1), the groups R¹ and R²are, independently of each other, a hydrogen atom or alkyl group, thegroup Q¹ is a saturated or unsaturated, bicyclic or tricyclic fusedhydrocarbon group which may be substituted, or a saturated orunsaturated, bicyclic or tricyclic fused heterocyclic group which may besubstituted, the group Q² is a single bond, the group Q⁵ in the group Q³is an alkylene group having 3 to 6 carbon atoms or a group—(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n are independently ofeach other 0 or 1, and A has the same meaning as defined above, thegroup Q⁴ is selected from 3 groups (i), (j) and (k) of theabove-described 12 groups, the group T⁰ is a carbonyl group orthiocarbonyl group, and the group T¹ is a group —C(═O)—C(═O)—N(R′)—,group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group—C(═S)—C(═S)—N(R′)—.

Stereoisomers or optical isomers derived from an asymmetric carbon atommay be present in the compounds of the present invention represented bythe general formula (1). However, these stereoisomers, optical isomersand mixtures thereof are all included in the present invention.

No particular limitation is imposed on salts of the compounds of thepresent invention represented by the general formula (1) so far as theyare pharmaceutically acceptable salts. However, specific examplesthereof include mineral acid salts such as hydrochlorides,hydrobromides, hydriodides, phosphates, nitrates and sulfates;benzoates; organic sulfonates such as methanesulfonates,2-hydroxyethanesulfonates and p-toluenesulfonates; and organiccarboxylates such as acetates, propanoates, oxalates, malonates,succinates, glutarates, adipates, tartrates, maleates, malates andmandelates. In the case where the compounds represented by the generalformula (1) have an acidic group, they may be salts of alkali metal ionsor alkaline earth metal ions. No particular limitation is imposed on thesolvates thereof so far as they are pharmaceutically acceptablesolvates. As specific examples thereof, however, may be mentionedhydrates and solvates with ethanol. When a nitrogen atom is present inthe general formula (1), such a compound may be converted to an N-oxidethereof.

As the compounds according to the present invention, are preferred thecompounds described in the following Examples and salts thereof as wellas the following compounds and salts thereof.

-   1)    3-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)[1,6]naphthyridine-7-carboxamide;-   2)    7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-fluorocinnoline-3-carboxamide;-   3)    7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4a,8a-dihydro-4H-1,2,4-benzoxadiazine-3-carboxamide;-   4)    N-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxamide;-   5)    7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-5-oxo-4,5-dihydro-1H-1,3,4-benzotriazepine-2-carboxamide;-   6)    6-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-oxo-3,4-dihydro-2(1H)cinnolinecarboxamide;-   7)    6-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-1,2,3,4-tetrahydroquinoline-2-carboxamide;-   8)    N-{(1R,2S,5S)-2-{[3-(3-chlorophenyl)-2-propinoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxamide;-   9)    N-{(1R,2S,5S)-2-[(4-chlorobenzoyl)amino]-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxamide;-   10)    N-{(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-carboxamide;-   11)    5-Chloro-N-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-({[5-(3-pyrrolidinyloxy)thiazol-2-yl]carbonyl}amino)cyclohexyl]indole-2-carboxamide;-   12)    N¹-(4-Chlorophenyl)-N²-((1S,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   13)    N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   14)    N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   15)    N¹-(4-Chlorophenyl)-N²-((1S,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   16)    N¹-(5-Chloropyridin-2-yl)-N²-((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclopentyl)ethanediamide;-   17)    N¹-(4-Chlorophenyl)-N²-((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclopentyl)ethanediamide;-   18)    N¹-(4-Chlorophenyl)-N²-((1R,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cycloheptyl)ethanediamide;-   19)    N¹-(5-Chloropyridin-2-yl)-N²-((1R,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cycloheptyl)ethanediamide;-   20)    N¹-(5-Chloropyridin-2-yl)-N²-((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cycloheptyl)ethanediamide;-   21)    N¹-(4-Chlorophenyl)-N²-((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cycloheptyl)ethanediamide;-   22)    N¹-(5-Chloro-6-methylpyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   23)    N¹-(5-Chloro-3-methylpyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   24)    N¹-(5-Chloro-4-methylpyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   25)    N¹-(4-Chloro-3-hydroxyphenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   26)    N¹-(4-Chloro-2-hydroxyphenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   27)    N¹-[4-Chloro-2-(fluoromethyl)phenyl]-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   28)    N¹-[4-Chloro-2-(methoxymethyl)phenyl]-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   29)    N-{(1R,2S,5S)-2-({[1-(4-Chloroanilino)cyclopropyl]carbonyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxamide;-   30)    N¹-(5-Chloropyridin-2-yl)-N²-((1R,2R,4R)-4-(hydroxymethyl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)ethanediamide;-   31)    N¹-(5-Chloropyridin-2-yl)-N²-((1R,2R,4S)-4-(hydroxymethyl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)ethanediamide;-   32)    N¹-((3R,4S)-1-Acetyl-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)-N²-(5-chloropyridin-2-yl)ethanediamide;-   33)    N¹-(5-Chloropyridin-2-yl)-N²-((3R,4S)-1-(methylsulfonyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamide;-   34)    N¹-{(1S,2R,4S)-2-{[(3-Chlorobenzothiophen-2-yl)carbonyl]amino}-4-[(dimethylamino)carbonyl]cyclohexyl}-N²-(5-chloropyridin-2-yl)ethanediamide;-   35)    N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbothioyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   36)    N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbothioyl]amino}cyclohexyl)ethanediamide;-   37)    N¹-(5-Chloropyridin-2-yl)-N²-((3R,4S)-1-(2-methoxyethanethioyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamide;-   38)    N¹-(5-Chloropyridin-2-yl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbothioyl]amino}piperidin-4-yl)ethanediamide;-   39)    N-[(3R,4S)-4-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;-   40)    N-[(3R,4S)-4-({2-[(5-Chloropyridin-2-yl)amino]-2-thioxoacetyl}amino)-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;-   41)    N¹-(4-Chlorophenyl)-N²-((3R,4S)-1-(2-methoxyethanethioyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamide;-   42)    N¹-(4-Chlorophenyl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbothioyl]amino}piperidin-4-yl)ethanediamide;-   43)    N-[(3R,4S)-4-{[2-[(4-Chloroanilino)-2-oxoethanethioyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;-   44)    N-[(3R,4S)-4-({2-[(4-Chlorophenyl)amino]-2-thioxoacetyl}amino)-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;-   45)    N¹-((1S,2R,4S)-4-(1-azetidinylcarbonyl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N²-(5-chloropyridin-2-yl)ethanediamide;-   46)    N¹-(5-Chloropyridin-2-yl)-N²-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1-pyrrolidinylcarbonyl)cyclohexyl]ethanediamide;-   47)    N¹-(5-Chloropyridin-2-yl)-N²-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1-piperidinylcarbonyl)cyclohexyl]ethanediamide;-   48)    N¹-(5-Chloropyridin-2-yl)-N²-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(4-morpholinylcarbonyl)cyclohexyl]ethanediamide;-   49)    N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(methylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   50)    N¹-{(1R,2S,5S)-2-({2-[(6-Chloropyridazin-3-yl)amino]-2-oxoethanethioyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide;-   51)    N¹-(4-Bromophenyl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamide;-   52)    N¹-(5-Chloropyridin-2-yl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[4-(pyridin-4-yl)benzoyl]amino}piperidin-4-yl)ethanediamide;-   53)    N¹-(5-Chloropyridin-2-yl)-N²-[(3R,4S)-1-(2-methoxyacetyl)-3-({[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl}amino)piperidin-4-yl]ethanediamide;-   54)    N¹-(5-Chloropyridin-2-yl)-N²-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-({[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl}amino)cyclohexyl]ethanediamide;-   55)    N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-oxoethane(methoxy)imidoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide;-   56)    N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-(methoxyimino)acetyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide;-   57)    N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   58)    N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(4,4-ethylene-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;-   59)    N-{(1R,2S,5S)-2-({[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;-   60)    N-{(1R,2S,5S)-2-{[(4-Chlorobenzyl)sulfonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;-   61)    N-{(1R,2S,5S)-2-[(2-{[(4-Chlorophenyl)sulfonyl]amino}acetyl)amino]-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide.

The preparation process of the diamine derivatives (1) according to thepresent invention will hereinafter be described.

[Preparation Process 1]

A compound represented by the general formula (1), a salt thereof, asolvate thereof, or an N-oxide thereof can be prepared in accordancewith, for example, the following process:

wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings as definedabove, and T¹ represents a carbonyl group.

A mixed acid anhydride, acid halide, activated ester or the like, whichis derived from carboxylic acid (3), may react with diamine (2), givingcompound (4). The resultant compound (4) may react with carboxylic acid(5) under the same conditions, giving compound (1) according to thepresent invention. In the above reaction steps, reagents and conditions,which are generally used in peptide synthesis, may be applied. The mixedacid anhydride can be prepared by, for example, reaction of achloroformate such as ethyl chloroformate or isobutyl chloroformate withcarboxylic acid (3) in the presence of a base. The acid halide can beprepared by treating carboxylic acid (3) with an acid halide such asthionyl chloride or oxalyl chloride. The activated ester includesvarious kinds of esters. Such an ester can be prepared by, for example,reaction of a phenol such as p-nitrophenol, N-hydroxybenzotriazol, orN-hydroxysccinimide with carboxylic acid (3) using a condensing agentsuch as N,N′-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Theactivated ester can also be prepared by reaction of carboxylic acid (3)with pentafluorophenyl trifluoroacetate or the like, reaction ofcarboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinophosphoniumhexafluorophosphite, reaction of carboxylic acid (3) with diethylcyanophosphonate (Shioiri method), reaction of carboxylic acid (3) withtriphenylphosphine and 2,2′-dipyridyl disulfide (Mukaiyama method) orthe like. The thus-obtained mixed acid anhydride, acid halide oractivated ester of carboxylic acid (3) may react with diamine (2) at−78° C. to 150° C. in the presence of a proper base in an inert solvent,giving compound (4). Thus-obtained compound (4) may react with a mixedacid anhydride, acid halide or activated ester of carboxylic acid (5)under the same conditions, giving compound (1) according to the presentinvention. The reagents and reaction conditions in the reaction ofcompound (4) with carboxylic acid (5) are the same as those in thereaction of diamine (2) with carboxylic acid (3).

As specific examples of the base used in each of the above mentionedstep, may be carbonates of alkali metals or alkaline earth metals, suchas sodium carbonate and potassium carbonate, alkali metal alkoxides suchas sodium ethoxide and potassium butoxide, alkali metal hydroxides suchas sodium hydroxide and potassium hydroxide, and hydrides of alkalimetals or alkaline earth metals, such as sodium hydride and potassiumhydride; organic metal bases exemplified by alkyllithium such asn-butyllithium, and dialkylaminolithium such as lithiumdiisopropylamide; organic metal bases exemplified by bis(silyl)amine,such as lithiumbis(trimethylsilyl)amide; and organic bases such aspyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

Examples of the inert solvent used in this reaction include alkyl halidetype solvents such as dichloromethane, chloroform and carbontetrachloride, etheric solvents such as tetrahydrofuran,1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene andtoluene, and amide solvents such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one. In addition to thesesolvent, a sulfoxide solvent such as dimethyl sulfoxide or sulfolane, aketone solvent such as acetone or methyl ethyl ketone, or the like maybe used in some cases.

[Preparation Process 2]

Compound (1) according to the present invention can also be prepared inaccordance with the following process:

wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings as definedabove, T¹ represents a carbonyl group, Boc represents atert-butoxycarbonyl group, and Boc-ON represents a2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.

As described above, diamine (2) is treated with Boc-ON (6) to preparecompound (7) in which one of 2 amino groups has been protected withtert-butoxycarbonyl group. The resultant compound (7) reacts withcarboxylic acid (5) and affords compound (8). Compound (8) issuccessively treated with an acid to give compound (9). Compound (9)then reacts with the carboxylic acid (3), giving compound (1) accordingto the present invention. Compound (7) can be prepared by a reaction at−10° C. to 40° C. in the presence of triethylamine in a solvent such asdichloromethane. Reaction of compound (7) with the mixed acid anhydride,acid halide or activated ester of the carboxylic acid (5) is carried outusing the same reagents and reaction conditions as those described inPreparation Process 1, whereby compound (8) can be prepared. Theresultant compound (8) is treated with trifluoroacetic acid or the likeat −20° C. to 70° C., whereby amine (9) can be prepared. In the reactionof the resultant amine (9) with carboxylic acid (3), the same reagentsand conditions as those described in Preparation Process 1 may be used.

By the way, the tert-butoxycarbonyl group of compound (7) may bereplaced by other amino-protecting groups. In this case, reagent (6) isalso changed to other reagents, and reaction conditions and the likeaccording to the reagents must be used. As examples of other protectinggroups for amino groups, may be mentioned alkanoyl groups such as anacetyl group, alkoxycarbonyl groups such as methoxycarbonyl andethoxycarbonyl groups, arylmethoxycarbonyl groups such asbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p- oro-nitrobenzyloxycarbonyl groups, arylmethyl groups such as benzyl andtriphenylmethyl groups, aroyl groups such as a benzoyl group, andarylsulfonyl groups such as 2,4-dinitrobenzenesulfonyl ando-nitrobenzenesulfonyl groups. These protecting groups may be chosen foruse according to the nature and the like of the compound of which aminogroup is to be protected. Upon leaving such a protecting group, reagentsand conditions may be employed according to the protecting group.

[Preparation Process 3]

Compound (1) according to the present invention can be prepared byreacting diamine (2) with sulfonyl halide (10) and then condensing thereaction product with carboxylic acid (5).

wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings as definedabove, T¹ represents a sulfonyl group, and X represents a halogen atom.

Diamine (2) reacts with sulfonyl halide (10) at −10° C. to 30° C. in thepresence of a base such as triethylamine in an inert solvent, givingcompound (4). The inert solvent and base may be suitably chosen for usefrom those described in Preparation Process 1. The resultant compound(4) is condensed with carboxylic acid (5) using the reagents andconditions described in Preparation Process 1, whereby compound (1)according to the present invention can be prepared. Sulfonyl halide (10)may be synthesized in a proper base in accordance with the publiclyknown process (WO96/10022, WOO/09480) or a process according to it.

[Preparation Process 4]

Compound (1) according to the present invention can also be prepared inaccordance with the following process:

wherein Q¹, Q², Q³, Q⁴, R¹, R² and X have the same meanings as definedabove, and T¹ represents a sulfonyl group.

More specifically, amine (9) may react with sulfonyl halide (10) at −10°C. to 30° C. in the presence of a base in an inert solvent, givingcompound (1). The inert solvent and base may be suitably chosen for usefrom those described in Preparation Process 1.

[Preparation Process 5]

In the compounds (1) according to the present invention, geometricalisomers of trans-form and cis-form in the relation between position 1and position 2 are present when Q³ is the following group:

wherein R³, R⁴ and Q⁵ have the same meanings as defined above, andnumerals 1 and 2 indicate positions.

The preparation processes of such compounds (1) having the trans-formand the cis-form will hereinafter be described.

<Preparation Process of Trans-Form>

wherein Q⁵, R³ and R⁴ have the same meanings as defined above.

As an example of preparation of trans-diol (12a) from cyclic alkene(11), conversion from, for example, cyclohexene to trans-cyclohexanediol(organic Synthesis, 1995, Vol. III, p. 217) is known. As an example ofpreparation of trans-diamine (2a) from trans-diol (12a), conversion fromtrans-cyclopentanediol to trans-cyclopentanediamine (WO98/30574) isreported. Trans-diamine (2a) can be prepared from the cyclic alkene (11)according to these reports.

Trans-diamine (2a) prepared in accordance with the above-describedprocess can be converted into trans-compound (1) by any of theabove-described Preparation Processes 1 to 4.

<Preparation Process of Cis-Form>

wherein Q⁵, R³ and R⁴ have the same meanings as defined above, andnumerals.

As an example of preparation of cis-diol (12b) from cyclic alkene (11),conversion from cyclohexene to cis-cyclohexanediol (J. Org. Chem., 1998,Vol. 63, p. 6094) and the like is known. As an example of preparation ofcis-diamine (2b) from cis-diol (12a), conversion fromcis-cyclopentanediol to cis-cyclopentanediamine (WO98/30574) and thelike is reported. Cis-diamine (2b) can be prepared from cyclic alkene(11) according to these reports.

Cis-diamine (2b) prepared in accordance with the above-described processcan be converted into the cis-compound (1) by any of the above-describedPreparation Processes 1 to 4.

[Preparation Process 6]

As described above, either cis-form or trans-form generated in Q³ may bepresent in the compounds (1) according to the present invention, and sogeometrical isomers are present. Further, optical isomers may be presentin the respective geometrical isomers. The preparation process of anoptically active substance will hereinafter be described.

wherein Q⁵, R¹, R², R³ and R⁴ have the same meanings as defined above,and R⁵⁰ represents a protecting group for amino group.

With respect to the preparation process of optically active aminoalcoholderivative (15) of 1,2-trans-form, for example, the preparation processof optically active 1,2-trans-2-aminocyclopentanol from cyclopenteneoxide or the preparation process of optically active1,2-trans-2-aminocyclohexanol from cyclohexene oxide is known(Tetrahedron: Asymmetry, 1996, Vol. 7, p. 843; J. Org. Chem., 1985, Vol.50, p. 4154; J. Med. Chem., 1998, Vol. 41, p. 38). When the amino groupof optically active aminoalcohol derivative (15) prepared by such analready known process or by applying such a process reacts with a properprotecting reagent, compound (16) can be produced. As a protecting groupcorresponding to R⁵⁰ in compound (16) is preferred, among the ordinaryacyl type protecting groups, an alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl group and the like,an arylmethoxycarbonyl group such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p- or o-nitrobenzyloxy-carbonyl group andthe like, or an arylsulfonyl group such as 2,4-dinitrobenzenesulfonyl,o-nitrobenzenesulfonyl group and the like. When the amino group isprotected with, for example, a tert-butoxycarbonyl group, aminoalcoholderivative (15) may react with di-tert-butyl dicarbonate at −78° C. to50° C. in an inert solvent, giving compound (16). The inert solvent maybe suitably chosen for use from those described in Preparation Process1.

Compound (16) may react with methanesulfonyl chloride at −78° C. to 50°C. in the presence of a base in an inert solvent, giving compound (17).The inert solvent may be suitably chosen for use from those described inPreparation Process 1. As the base, is preferred an organic base such aspyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU) and the like.

Compound (17) may react with sodium azide at −10° C. to 150° C. in aproper solvent, giving compound (18). As the solvent, an amide solventsuch as N,N-dimethylformamide, N,N-dimethylacetamide orN-methylpyrrolidin-2-one, an alcoholic solvent such as methanol orethanol, an etheric solvent such as tetrahydrofuran, 1,2-dimethoxyethaneor dioxane, benzenoid solvent such as toluene, a carbon halogenide suchas dichloromethane, chloroform or carbon tetrachloride, acetone,dimethyl sulfoxide, or a mixed solvent of such a solvent with water issuitable.

As a process for converting azide derivative (18) into compound (7a),there are many processes such as a process of conducting hydrogenationwith a palladium catalyst, Raney nickel catalyst or platinum catalyst, areaction using a reducing agent such as lithium aluminum hydride, sodiumborohydride or zinc borohydride, a reaction using zinc in the presenceof nickel chloride or cobalt chloride, a reaction usingtriphenylphosphine and the like. Suitable reaction conditions may beselected according to the nature of the compound. For example, azidederivative (18) is hydrogenated at a temperature of −10° C. to 70° C.using 1 to 20% palladium carbon as a catalyst in a proper solvent,whereby compound (7a) can be prepared. The hydrogen pressure may beraised higher than atmospheric pressure. As the solvent, an alcoholicsolvent such as methanol or ethanol, an etheric solvent such astetrahydrofuran, 1,2-dimethoxyethane or dioxane, an amide solvent suchas N,N-dimethylformamide, N,N-dimethylacetamide orN-methylpyrrolidin-2-one, an ester solvent such as ethyl acetate, aceticacid, hydrochloric acid, water, a mixed solvent thereof and the like issuitable.

Optically active amine (7a) prepared in accordance with theabove-described process can be converted to optically active compound(1) in accordance with the above-described Preparation Process 2.Antipode (1) of optically active substance (1) obtained from opticallyactive amine (7a) may also be prepared in accordance with a similarprocess.

Optically active compound (1) may be prepared by separating racemiccompound (1) through a column composed of an optically active carrier.It is also possible to separate intermediate (2), (4), (7), (8) or (9)for preparing racemic compound (1) through a column composed of anoptically active carrier to isolate optically active intermediate (2),(4), (7), (8) or (9), and then prepare optically active compound (1) inaccordance with any of Preparation Processes 1 to 4. As a process forisolating optically active compound (1), optically active intermediate(2), (4), (7), (8) or (9), a process of fractionally crystallizing asalt with an optically active

carboxylic acid, or a process of fractionally crystallizing a salt withan optically active base on the contrary may be used.

[Preparation Process 7]

Among the compounds (1) according to the present invention, apreparation process of compound (1c) containing heteroatom(s) in thegroup Q³ will hereinafter be described in detail.

A compound represented by the general formula (1c), a salt thereof, asolvate thereof, or an N-oxide thereof can be prepared in accordancewith, for example, the following process:

wherein Q¹, Q², Q³, Q⁴, R³, R⁴, A, m and n have the same meanings asdefined above, and T¹ represents a carbonyl group.

A mixed acid anhydride, acid halide, activated ester or the like, whichis derived from carboxylic acid (3), may react with compound (2c),giving compound (4c). The resultant compound (4c) may react withcarboxylic acid (5) under the same conditions, giving compound (1c)according to the present invention.

In the above reaction steps, reagents and conditions, which aregenerally used in peptide synthesis, may be applied. The mixed acidanhydride can be prepared by, for example, reaction of a chloroformatesuch as ethyl chloroformate or isobutyl chloroformate with carboxylicacid (3) in the presence of a base. The acid halide can be prepared bytreating carboxylic acid (3) with an acid halide such as thionylchloride or oxalyl chloride. The activated ester includes various kindsof esters. Such an ester can be prepared by, for example, reaction of aphenol such as p-nitrophenol, N-hydroxybenzotriazol, orN-hydroxysccinimide with carboxylic acid (3) using a condensing agentsuch as N,N′-dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Theactivated ester can also be prepared by reaction of carboxylic acid (3)with pentafluorophenyl trifluoroacetate or the like, reaction ofcarboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinophosphoniumhexafluorophosphite, reaction of carboxylic acid (3) with diethylcyanophosphonate (Shioiri method), reaction of carboxylic acid (3) withtriphenylphosphine and 2,2′-dipyridyl disulfide (Mukaiyama method) orthe like. The thus-obtained mixed acid anhydride, acid halide oractivated ester of carboxylic acid (3) may react with compound (2c) at atemperature under cooling to a temperature under heating in the presenceof a proper base in an inert solvent, giving compound (4c).Thus-obtained compound (4c) may react with a mixed acid anhydride, acidhalide or activated ester of carboxylic acid (5) under the sameconditions, giving compound (1c) according to the present invention. Thereagents and reaction conditions in the reaction of compound (4C) withcarboxylic acid (5) are the same as those in the reaction of diamine(2c) with carboxylic acid (3).

As specific examples of the base used in each of the above step, may bementioned carbonates of alkali metals or alkaline earth metals, such assodium carbonate and potassium carbonate, alkali metal alkoxides such assodium ethoxide and potassium butoxide, alkali metal hydroxides such assodium hydroxide and potassium hydroxide, and hydrides of alkali metals,such as sodium hydride and potassium hydride; organic metal basesexemplified by alkyllithium such as n-butyllithium, and organic metalbases exemplified by dialkylaminolithium such as lithiumdiisopropylamide; organic metal bases of bis(silyl)amine, such aslithium-bis(trimethylsilyl)amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU) or the like.

Examples of the inert solvent used in this reaction include alkyl halidetype solvents such as methylene chloride and chloroform, ethericsolvents such as tetrahydrofuran and 1,4-dioxane, aromatic solvents suchas benzene and toluene, and amide solvents such asN,N-dimethylformamide. In addition to these solvent, a sulfoxide solventsuch as dimethyl sulfoxide, a ketone solvent such as acetone, or thelike may be used in some cases.

In the above-described preparation steps, processes such as attachingand leaving of a protecting group, and conversion of a functional groupcan be suitably applied, thereby preparing compound (1c).

As the protecting group for amino group, it is only necessary to use aprotecting group, which is generally used as a protecting group foramino group in syntheses of organic compounds, particularly, peptidesynthesis. As examples thereof, may be mentioned alkoxycarbonyl groupssuch as tert-butoxycarbonyl, methoxycarbonyl and ethoxycarbonyl groups,arylmethoxycarbonyl groups such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl and p- or o-nitrobenzyloxycarbonyl group,arylmethyl groups such as benzyl, 4-methoxybenzyl and triphenylmethylgroups, alkanoyl groups such as formyl and acetyl groups, aroyl groupssuch as a benzoyl group, and arylsulfonyl groups such as2,4-dinitrobenzenesulfonyl and o-nitrobenzenesulfonyl groups.

As the protecting group for hydroxyl group, it is only necessary to usea protecting group for hydroxyl group, which is generally used insyntheses of organic compounds. As examples thereof, may be mentionedalkoxymethyl groups such as a methoxymethyl group, arylmethyl groupssuch as benzyl, 4-methoxybenzyl, triphenylmethyl groups, alkanoyl groupssuch as an acetyl group, aroyl groups such as a benzoyl group, and atert-butyldiphenylsilyloxy group. A carboxyl group can be protected asan ester with an alkyl group such as a methyl group, ethyl group,tert-butyl group or an arylmethyl group such as a benzyl group. Theattaching and leaving of the protecting group may be conducted inaccordance with a method known per se in the art.

Compound (1c) according to the present invention can be converted intovarious derivatives by converting its functional group. For example, acompound in which A is a nitrogen atom having no substituent can beconverted into an amide compound by acylation using a mixed acidanhydride, acid halide, activated ester or the like in accordance withordinary organic chemical methods, a sulfonamide compound by reactionwith a sulfonyl halide, an N-alkyl compound by reaction with an alkylhalide, an N-aryl compound by reaction with an aryl halide or acarbamate compound by reaction with an isocyanate. Incidentally, thecompound in which A is a nitrogen atom having no substituent can beprepared by, for example, treating compound (1c) prepared from diamine(2c), in which A has been protected with tert-butoxycarbonyl group, inaccordance with Preparation Process 7 with an acid.

The compounds according to the present invention thus prepared can beisolated and purified by publicly known methods, for example,extraction, precipitation, fractional chromatography, fractionalcrystallization, recrystallization, etc. The compounds according to thepresent invention can be converted into desired salts in accordance withordinary salt-forming reactions.

Optical isomers derived from an asymmetric carbon atom are present inthe compounds of the present invention. Such an optically active isomercan be prepared by the process of preparing from optically activediamine (2c), and besides, a process of forming an optically activeamine or acid and a salt from racemic compound (1c) and fractionallycrystallizing it, a process of separating it by column chromatographyusing an optically active carrier.

Compound (1c), in which T¹ is a sulfonyl group, can be prepared bychanging carboxylic acid (3) to sulfonyl halide (10) in the reaction ofcompound (2c) with carboxylic acid (3).

[Preparation Process 8]

Compound (1c) according to the present invention can also be prepared inaccordance with the following process:

wherein Q¹, Q², Q⁴, R³, R⁴, A, m and n have the same meanings as definedabove, T¹ represents a carbonyl group, and R⁵¹ and R⁶¹ representprotecting groups for amino group.

Compound (21) can be prepared by removing the protecting group R⁶¹ ofcompound (19) obtained by protecting the amino groups of compound (2c).No particular limitation is imposed on the protecting groups for aminoacid illustrated as R⁵¹ and R⁶¹ so far as they are groups generally usedin protection of the amino group. However, as typical examples thereof,may be mentioned the protecting groups for amino group described inPreparation Process 7. In this case, R⁵¹ and R⁶¹ are required to beprotecting groups capable of leaving by different methods or conditionsfrom each other. As typical examples thereof, may be mentioned acombination that R⁵¹ is a tert-butoxycarbonyl group, and R⁶¹ is abenzyloxycarbonyl group. These protecting groups may be chosen for useaccording to the nature and the like of the compound of which aminogroups are to be protected. Upon leaving such a protecting group,reagents and conditions may be employed according to the protectinggroup.

Compound (21) can also be prepared by converting the hydroxyl group inaminoalcohol derivative (20) into an amino group. As an example of thepreparation of aminoalcohol derivative (20), is known conversion ofmethionine into 3-hydroxy-4-aminothiopyrane-1,1-dioxide (TetrahedronLett., Vol. 37, p. 7457, 1996) or the like.

As a process for converting the hydroxyl group in aminoalcoholderivative (20) into an amino group, may be mentioned a process in whichaminoalcohol derivative (20) may react with methanesulfonyl chloride,p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride or thelike, the resultant product may then react with ammonia, a primaryarylalkylamine such as benzylamine, p-methoxybenzylamine or2,4-dimethoxybenzylamine, a secondary arylalkylamine such asdibenzylamine, or a hydroxylamine such as N-benzylhydroxylamine orN,O-dibenzylhydroxylamine, and benzyl group or the like is then removedas needed, thereby preparing diamine (21). Aminoalcohol derivative (20)can also be converted into diamine (21) by reacting it with phthalimideor succinimide in accordance with the reaction with triphenylphosphineand ethyl azodicarboxylate (Mukaiyama method) or the like, and thentreating the reaction product with hydrazine, N-methylhydrazine or thelike. When A in the formula is SO₂, and n is 0, diamine (21) can beprepared by adding ammonia, a primary arylalkylamine such as ammonia,benzylamine, p-methoxybenzylamine or 2,4-dimethoxybenzylamine, asecondary arylalkylamine such as dibenzylamine, or a hydroxylamine suchas N-benzylhydroxylamine or N,O-dibenzylhydroxylamine to anα,β-unsaturated cyclic sulfone formed by reacting aminoalcoholderivative (20) with methanesulfonyl chloride, p-toluenesulfonylchloride, trifluoromethanesulfonic anhydride or the like and thentreating the reaction product with a proper base or directly reactingaminoalcohol derivative (20) with triphenylphosphine and ethylazodicarboxylate, and removing the benzyl group or the like as needed.

The resultant diamine (21) may react with carboxylic acid (3), givingcompound (22). The protecting group R⁵¹ is successively removed, givingcompound (4c). Compound (4c) may react with carboxylic acid (5), givingcompound (1c) according to the present invention. The reagents andreaction conditions in the reaction of compound (21) with carboxylicacid (3) and the reaction of compound (4C) with carboxylic acid (5) maybe the same as those described in Preparation Process 7.

Similarly, compound (1c) in which T¹ is a sulfonyl group can be preparedby changing carboxylic acid (3) to sulfonyl halide (10) in the reactionof compound (21) with carboxylic acid (3).

[Preparation Process 9]

A typical preparation process of intermediate (2c) for preparationdescribed in Preparation Process 7 will be described.

wherein R³, R⁴, A, m and n have the same meanings as defined above.

As preparation processes of diol derivative (23), are known, forexample, conversion of 1,2,3,6-tetrahydropyridine into1-benzyloxycarbonyl-3,4-cis-dihydroxypyrrolidine (Japanese PatentApplication Laid-Open No. 138264/1995), conversion of L-tartaric acidinto (R,R)-tetrahydrofurandiol or (R,R)—N-benzylpyrrolidinediol(Tetrahedron: Asymmetry, Vol. 8, p. 1861, 1997) and the like. Diolderivative (23) can be prepared by using such an already known processor applying such a process and removing a protecting group or convertinga functional group as needed.

Diol derivative (23) may react with methanesulfonyl chloride at atemperature under cooling to room temperature in the presence of a basein an inert solvent, giving compound (24). The inert solvent may besuitably chosen for use from those described in Preparation Process 7.However, particularly preferred are alkyl halide type solvents such asmethylene chloride and chloroform, and etheric solvents such astetrahydrofuran and 1,4-dioxane. As the base, is preferred an organicbase such as pyridine, 2,6-lutidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine ordiazabicyclo-[5.4.0]undec-7-ene (DBU).

Compound (24) may react with sodium azide at a temperature under coolingto a temperature under heating in a proper solvent, giving azidederivative (25). As the solvent, an amide solvent such asN,N-dimethylformamide, N-methylpyrrolidin-2-one, an alcoholic solventsuch as methanol or ethanol, an etheric solvent such as tetrahydrofuranor 1,4-dioxane, aromatic solvent such as benzene or toluene, a carbonhalogenide such as methylene chloride or chloroform, dimethyl sulfoxide,acetone, or the like is suitable. Such a solvent may be a mixed solventwith water.

As a process for converting azide derivative (25) into compound (2c),there are many processes such as a process of conducting hydrogenationwith a palladium catalyst, Raney nickel catalyst or platinum catalyst, areaction using a reducing agent such as lithium aluminum hydride orsodium borohydride, a reaction using zinc in the presence of nickelchloride or cobalt chloride, and a reaction using triphenylphosphine ofthe like. Suitable reagents and reaction conditions may be selectedaccording to the nature of the compound. The hydrogen pressure may beraised higher than atmospheric pressure. As the solvent, an alcoholicsolvent such as methanol or ethanol, an etheric solvent such astetrahydrofuran or 1,4-dioxane, an amide solvent such asN,N-dimethylformamide or N-methylpyrrolidin-2-one, an ester solvent suchas ethyl acetate, acetic acid, hydrochloric acid, water, a mixed solventthereof or the like is suitable. Compound (1c) according to the presentinvention can be derived from diamine derivative (2c) prepared inaccordance with the above-described process in accordance withPreparation Process 7.

When diol derivative (23) is trans-3,4-dihydroxytetrahydrofuran ortrans-1-substituted 3,4-dihydroxypyrrolidine and the like, opticallyactive substances are present. These optically active diol derivatives(23) can be converted into optically active diamine derivatives (2c),and further into optically active compounds (1c) according to thepresent invention in accordance with Preparation Process 7.

[Preparation Process 10]

A typical preparation process of optically active compounds (30), (31)and (32) included in compound (19) described in Preparation Process 8will be described. Incidentally, the position of an asymmetric carbonatom shown in the following preparation scheme is indicated by way ofexample.

wherein m, n, R³, R⁵¹ and R⁶¹ have the same meanings as defined above,and R⁷¹ represents a protecting group for carboxyl group.

Optically active α,β-unsaturated ester derivative (26) can be preparedin accordance with the process described in literature (J. Org. Chem.,Vol. 61, p. 581, 1996; J. Org. Chem., Vol. 57, p. 6279, 1992, etc.) orby applying such a process. Optically active α,β-unsaturated esterderivative (26) may react with an amine at a temperature under cooling,or under heating in a proper solvent, giving diastereomers (27a) and(27b). The amine may be suitably chosen for use from those described inPreparation Process 8. The solvent is desirably an organic solventunreactive to a substrate, product or reagent, particularly, analcoholic solvent such as methanol or ethanol, or an etheric solventsuch as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like.Diastereomers (27a) and (27b) can also be prepared by reaction ofα,β-unsaturated ester derivative (26) with an organometallic base suchas lithium N-benzyl(trimethylsilyl)amide and the like by applying theprocess described in literature (J. Org. Chem., Vol. 63, p. 7263, 1998).The diastereomers may be separated to use, for example, diastereomer(27a) in the next reaction.

Compound (27a) is treated with an acid at a temperature under cooling,or under heating in a proper solvent, giving compound (28). Examples ofthe acid used include hydrochloric acid, sulfuric acid, Lewis acids suchas boron trifluoride, trifluoroacetic acid, p-toluenesulfonic acid orthe like. As the solvent, is used water or an alcoholic solvent such asmethanol or ethanol. Such a solvent may be a mixed solvent with water.In this reaction, the protecting group R⁶¹ may be left in some cases. Insuch a case, such a compound is required to react with a properprotecting reagent for amino group as needed.

Compound (28) may be treated with an acid at a temperature undercooling, or under heating in a proper solvent, giving optically activecompound (30). The acid used may be suitably chosen for use from theacids mentioned above, with a Lewis acid such as boron trifluoride, orp-toluenesulfonic acid or the like being particularly preferred. As thesolvent used in the reaction, is used an etheric solvent such as1,4-dioxane or tetrahydrofuran, or an aromatic solvents such as benzeneor toluene. Compound (30) can also be prepared from azide derivative(29). As examples of the preparation of optically active azidederivative (29), are known conversion of L-asparagic acid into(R,R)-(3S,4S)-3-amino-4-azide-5-oxotetrahydrofuran (Can. J. Chem., Vol.71, p. 1047, 1993) and the like. Optically active azide derivative (29)can be prepared by using such an already known process or applying sucha process and removing a protecting group or converting a functionalgroup as needed. The azide in azide derivative (29) may be reduced intoan amino group, and the resultant product may react with a properprotecting reagent for amino group, giving compound (30). The reagentsand reaction conditions used in the reduction of azide (29) may be thesame as those described in the process of converting azide derivative(25) into compound (2c).

The hydroxyl group portion of compound (28) may be converted into anamino group and then treated with a base, giving compound (31). Theconversion of the hydroxyl group in compound (28) into the amino groupcan be performed in accordance with, for example, Preparation Process 8.Compound (31) can also be prepared by treating alcohol derivative (28)with an oxidizing agent and then reductively aminating the resultantaldehyde derivative. Specific preferable examples of the oxidizing agentused in the above reaction include pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), sulfur trioxide pyridine complexes or thelike. Example of the amine include primary alkylamines such as ammonia,methylamine and ethylamine, and primary arylalkylamine such asbenzylamine, p-methoxybenzylamine and 2,4-dimethoxybenzylamine. As thereducing process, there are a process of conducting hydrogenation with apalladium catalyst, Raney nickel catalyst or platinum catalyst, areaction using a reducing agent such as sodium borohydride, sodiumtriacetoxyborohydride or sodium cyanoborohydride, and suitable reagentsand reaction conditions may be selected according to the nature of thecompound or the like. The base used in the above process may be suitablychosen for use from those described in Preparation Process 7. Compound(31) can also be prepared by using compound (30) and an amine inaccordance with the process described in literature (Tetrahedron Lett.,Vol. 41, p. 1141, 2000; Heterocycles, Vol. 53, p. 173, 2000) or byapplying such a process. Examples of the amine used include primaryalkylamines such as ammonia, methylamine and ethylamine, and primaryarylalkylamine such as benzylamine and p-methoxybenzyl-amine.

Compound (31) may be treated with a reducing agent at a temperatureunder cooling to a temperature under heating in a solvent, givingcompound (32). Examples of the reducing agent includeborane.tetrahydrofuran complexes, borane.methyl sulfide complexes,lithium aluminum hydride. However, suitable reagents and reactionconditions may be selected according to the nature of the compound orthe like. The solvent is desirably an organic solvent unreactive to asubstrate, product, reagentor the like, particularly, an etheric solventsuch as tetrahydrofuran or 1,4-dioxane.

Optically active substances (1c) of the compounds according to thepresent invention can be derived from the compounds (30), (31) and (32)prepared by the processes described above.

In the above-described preparation scheme, one of optically activesubstances has been described by way of example. However, otheroptically active substances different in conformation from each othermay also be prepared in accordance with similar preparation schemes byrespectively using starting materials different in conformation fromeach other.

[Preparation Process 11]

Compound (1) in which T¹ is a group —CO—CO—N(R′)—, in which R′ has thesame meaning as defined above, can be prepared in accordance with thefollowing scheme:

wherein Q¹, Q², Q³, Q⁴, R¹, R² and R′ have the same meanings as definedabove, and T¹ represents a group —CO—CO—N(R′)—, in which R′ has the samemeaning as defined above.

An acid halide, activated ester or the like, which is derived fromcarboxylic acid (33), may react with diamine (2), giving compound (4).The resultant compound (4) may react with carboxylic acid (5) under thesame conditions, giving compound (1) according to the present invention.In the above reaction steps, reagents and conditions, which aregenerally used in peptide synthesis, may be applied. The acid halide canbe prepared by treating carboxylic acid (33) with an acid halide such asthionyl chloride or oxalyl chloride. The activated ester includesvarious kinds of esters. Such an ester can be prepared by, for example,reaction of a phenol such as p-nitrophenol, N-hydroxybenzotriazol, orN-hydroxysccinimide with carboxylic acid (33) using a condensing agentsuch as N,N′-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Theactivated ester can also be prepared by reaction of carboxylic acid (33)with pentafluorophenyl trifluoroacetate or the like, reaction ofcarboxylic acid (33) with 1-benzotriazolyloxytripyrrolidinophosphoniumhexafluorophosphite, reaction of carboxylic acid (33) with diethylcyanophosphonate (Shioiri method), reaction of carboxylic acid (33) withtriphenylphosphine and 2,2′-dipyridyl disulfide (Mukaiyama method) orthe like. The thus-obtained mixed acid anhydride, acid halide oractivated ester of carboxylic acid (33) may react with diamine (2) at−78° C. to 150° C. in the presence of a proper base in an inert solvent,giving compound (4). Thus-obtained compound (4) may react with a mixedacid anhydride, acid halide or activated ester of carboxylic acid (5)under the same conditions, giving compound (1) according to the presentinvention. The reagents and reaction conditions in the reaction ofcompound (4) with carboxylic acid (5) are the same as those in thereaction of diamine (2) with carboxylic acid (33). The bases andsolvents used in the above respective steps may be suitably chosen fromthose described in Preparation Process 1.

When compound (1) in which Q³ is the following group:

wherein R³, R⁴ and Q⁵ have the same meanings as defined above, andnumerals 1 and 2 indicate positions, and the relation between position 1and position 2 is a trans-form or cis-form, is prepared, it is onlynecessary to use diamine (2a) or (2b) described in Preparation Process5.

When compound (1) in which a heteroatom such as a nitrogen atom, oxygenatom or sulfured atom is contained in Q⁵ is prepared, it is onlynecessary to change carboxylic acid (3) to carboxylic acid (33) in thereaction of compound (2c) with carboxylic acid (3) as described inPreparation Process 7. Namely, compound (1) in which a heteroatom iscontained in Q⁵ in the following reaction scheme, i.e., compound (1c)can be prepared.

wherein Q¹, Q², Q⁴, R³, R⁴, R′, A, m and n have the same meanings asdefined above, and T¹ represents a group —CO—CO—N(R′)—, in which R′ hasthe same meaning as defined above.

[Preparation Process 12]

Compound (1) in which T¹ is a group —CO—CO—N(R′)—, in which R′ has thesame meaning as defined above, can also be prepared in accordance withthe following scheme:

wherein Q¹, Q², Q³, Q⁴, R¹, R² and R′ have the same meanings as definedabove, and T¹ represents a group —CO—CO—N(R′)—, in which R′ has the samemeaning as defined above.

In the reaction of amine (9) with carboxylic acid (33), the samereagents and conditions as those described in Preparation Process 1 maybe used.

Amine (9) used herein can also be prepared in accordance with thefollowing scheme shown as a preparation scheme of amine (41) in additionof the scheme described in Preparation Process 2.

wherein R³, R⁴, Q¹, Q² and Q⁵ have the same meanings as defined above,and R⁵² represents a protecting group for amino group.

Compound (34) in the above preparation scheme can be prepared bytreating a cycloalkene with perbenzoic acid or a derivative thereof andthe like in a solvent such as methylene chloride to epoxidate it.Ordinary conditions for epoxidation of an alkene may be applied to theconditions of this reaction. Compound (34) can also be prepared inaccordance with the process described in J. Org. Chem., Vol. 61, pp.8687-8691 (1996) or a process corresponding thereto.

Compound (34) may react with sodium azide or the like in accordance witha method known per se in the art, giving azide (35). Azide (35) may becatalytically reduced, and the amino group of the resultant compound maybe protected, giving compound (36). As examples of the protecting groupfor amino group in this reaction, may be mentioned those described inPreparation Process 2. Compound (36) may be converted into azide (38) ina similar manner to the process described Preparation Process 5, and theprotecting group for the amino group thereof may be left, givingcompound (39). Compound (39) may react with carboxylic acid (5), givingcompound (40).

The compound (40) may then be catalytically reduced, giving compound(41).

[Preparation Process 13]

Compound (1) in which T¹ is a group —CO—CO—N(R′)—, in which R′ has thesame meaning as defined above, can also be prepared by changing thereaction of compound (9) with carboxylic acid (3) in the schemedescribed in Preparation Process 2 to a reaction of compound (9) withcompound (33).

wherein Q¹, Q², Q³, Q⁴, R¹, R² and R′ have the same meanings as definedabove, and T¹ represents a group —CO—CO—N(R′)—, in which R′ has the samemeaning as defined above.

As the reaction conditions, may be applied those described inPreparation Process 2.

When compound (1) in which Q³ is the following group:

wherein R³, R⁴ and Q⁵ have the same meanings as defined above, andnumerals 1 and 2 indicate positions, and a heteroatom such as a nitrogenatom, oxygen atom or sulfured atom is contained in Q⁵ is prepared, it isonly necessary to change carboxylic acid (3) to carboxylic acid (33) inthe reaction of compound (21) with carboxylic acid (3) as described inPreparation Process 8. Namely, compound (1) in which a heteroatom iscontained in Q⁵ in the following reaction scheme, i.e., compound (1c)can be prepared.

wherein Q¹, Q², Q⁴, R³, R⁴, R′, A, m and n have the same meanings asdefined above, and T¹ represents a group —CO—CO—N(R′)—, in which R′ hasthe same meaning as defined above, and R⁵¹ represents a protecting groupfor amino group.

[Preparation Process 14]

Compound (1) in which T¹ is a group —CO-A¹-N(R″)—, in which R″represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group,and A¹ represents an alkylene group having 1 to 5 carbon atoms, whichmay be substituted, can be prepared by reaction of compound (9)described in Preparation Process 2 with Q⁴-N(R″)-A¹-CO₂H (42) at −55° C.to 50° C. using a condensing agent in an inert solvent. As examples ofthe condensing agent, may be mentioned N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or the like.As examples of the inert solvent, may be mentioned alkyl halide typesolvents such as methylene chloride, chloroform and carbontetrachloride, etheric solvents such as tetrahydrofuran,1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene andtoluene, and amide solvents such as N,N-dimethylformamide.

wherein Q¹, Q², Q³, Q⁴, R¹, R² and R″ have the same meanings as definedabove, and T¹ represents a group —CO-A¹-N(R″)—, in which R″ represents ahydrogen atom, hydroxyl group, alkyl group or alkoxy group, and A¹represents an alkylene group having 1 to 5 carbon atoms, which may besubstituted.

Compound (42) described in the preparation process described above canbe prepared by, for example, reacting an arylamine such as4-chloroaniline with an ester of a bromoalkanoic acid at 40 to 120° C.in the presence of a base such as potassium carbonate in a solvent suchas acetonitrile or N,N-dimethylformamide and then hydrolyzing the esterwith an alkali such as lithium hydroxide, potassium hydroxide or sodiumhydroxide. Compound (42) may be used in reaction in the form of a saltsuch as a potassium salt as it is.

[Preparation Process 15]

Compound (1) in which T′ is a group —C(═O)—NH— or a group —C(═S)—NH—,can be prepared by reaction of compound (9) described in PreparationProcess 2 with isocyanate (Q⁴-N═C═O) or isothiocyanate (Q⁴-N═C═S) at−20° C. to 50° C. in an inert solvent. A typical examples of the innersolvent is described in Preparation Process 14. When isocyanate orisothiocyanate is not commercialized, isocyanate or isothiocyanate canbe synthesized using ordinary methods.

wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings as definedabove, and T¹ represents a group —C(═O)—NH— or group —C(═S)—NH—.

[Preparation Process 16]

Compound (1) in which T¹ is a group —CO—NH—NH— can be prepared byreaction of compound (9) described in Preparation Process 2 withQ⁴-NH—NH—CO₂Ph (43) at room temperature to 150° C. in an inert solventin the presence of a base if necessary. As typical examples of the inertsolvent, may be mentioned acetonitrile and N,N-dimethylformamide, andbesides those described in Preparation Process 14. As examples of thebase, may be mentioned pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings as definedabove, T¹ represents a group —CO—NH—NH— and ph represents phenyl group.

Compound (43) described in the preparation process described above canbe prepared by, for example, reacting an arylhydrazine such as4-chlorophenylhydrazine with diphenyl carbonate at room temperature to120° C. in a solvent such as acetonitrile, N,N-dimethylformamide,methylene chloride, chloroform, tetrahydrofuran, 1,2-dimethoxyethane,dioxane, benzene or toluene.

[Preparation Process 17]

Compound (1) in which T¹ is a group —CO-A²-CO—, in which A² represents asingle bond or alkylene group having 1 to 5 carbon atoms can be preparedby reaction of compound (9) described in Preparation Process 2 withQ⁴-CO-A²-CO₂H (44) at −50° C. to 50° C. using a condensing agent in aninert solvent. As examples of the condensing agent, may be mentionedN,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or the like.As examples of the solvent, may be mentioned those described inPreparation Process 16 or the like.

wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings as definedabove, and T¹ represents a group —CO-A²-CO—, in which A² represents asingle bond or alkylene group having 1 to 5 carbon atoms.

When A² is a single bond, compound (44) described in the preparationprocess described above can be prepared by, for example, hydrolyzing acompound (for example, Q⁴-CO—CO₂Et) prepared by the Friedel-Craftsreaction of an aromatic hydrocarbon such as chlorobenzene or an aromaticheterocyclic compound such as thiophene with a chloroxoacetate (forexample, ClCO—CO₂Et) using an alkali such as lithium hydroxide,potassium hydroxide or sodium hydroxide.

When A² is a methylene group, compound (44) can be prepared by, forexample, hydrolyzing a ketoester derivative (for example,Q⁴-CO—CH₂—CO₂Et) obtained by reaction of an arylcarbonyl chloride suchas 4-chlorobenzoyl chloride or a heteroarylcarbonyl chloride such asthiophenecarbonyl chloride with potassium malonic monoestermonocarboxylate in the presence of magnesium chloride and triethylaminewith an alkali such as lithium hydroxide, potassium hydroxide or sodiumhydroxide. The ketoester derivative may be used in the above reactionwith compound (9) in the form of a carboxylic acid obtained byhydrolysis after conversion of its carbonyl group into ethyleneketal.When A² is an alkylene group having at least 2 carbon atoms, compound(44) can be prepared by, for example, hydrolyzing a ketoester derivative(for example, Q⁴-CO-A²-CO₂Et) obtained by the Friedel-Crafts reaction ofan aromatic hydrocarbon such as benzene or an aromatic heterocycliccompound such as thiophene with an alkylenedicarboxylic monoestermonochloride using an alkali such as lithium hydroxide, potassiumhydroxide or sodium hydroxide.

[Preparation Process 18]

Compound (1) in which T¹ is a group —CO-A³-CO—NH—, in which A³represents an alkylene group having 1 to 5 carbon atoms can be preparedby reaction of compound (9) described in Preparation Process 2 withQ⁴-NH—CO-A³-CO₂H (45) at −50 to 50° C. using a condensing agent in aninert solvent. As examples of the condensing agent, may be mentionedN,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and thelike. Examples of the inert solvent include alkyl halide type solventssuch as methylene chloride, chloroform, carbon tetrachloride, ethericsolvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane,aromatic solvents such as benzene and toluene, and amide solvents suchas N,N-dimethylformamide.

wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings as definedabove, and T¹ represents a group —CO-A³-O—, in which A³ represents analkylene group having 1 to 5 carbon atoms.

Compound (45) can be prepared by hydrolyzing a compound (for example,Q⁴-NH—CO-A³-CO₂Et) obtained by reaction of an arylamine such as4-chloroaniline or a heteroarylamine such as aminopyridine correspondingto Q⁴-NH₂ with potassium alkylenedicarboxylic monoester monocarboxylateat −50 to 50° C. using a condensing agent in an inert solvent with analkali such as lithium hydroxide, potassium hydroxide or sodiumhydroxide.

[Preparation Process 19]

Compound (1) in which T¹ is a group —CS—CO—N(R′)—, in which R¹ has thesame meaning as defined above can be prepared in accordance with thefollowing scheme:

wherein Q¹, Q², Q³, Q⁴, R¹, R² and R′ have the same meanings as definedabove, and T¹ represents a group —CS—CO—N(R′)—, in which R′ has the samemeaning as defined above.

More specifically, sodium thiosulfate (46) and compound (9) may bedissolved or dispersed in a solvent and heated, giving compound (1)according to the present invention. The reaction temperature ispreferably 80 to 200° C., particularly preferably about 150° C. As thesolvent used in this reaction, may be mentioned water, alcohols such asmethanol and ethanol, basic solvents such as pyridine andN-methylmorpholine, alkyl halide type solvents such as methylenechloride, chloroform, etheric solvents such as tetrahydrofuran,1,2-dimethoxyethane and dioxane, and amide solvents such asN,N-dimethylformamide. These solvents may be suitably mixed for use. Asexamples of mixed solvents, may be mentioned a mixed solvent of methanoland methylene chloride or the like. In this reaction, the solvent is notnecessarily refluxed. For example, when the mixed solvent of methanoland methylene chloride is used, a reaction solution (or a reactionmixture) is heated at an external temperature of 150° C. to distill offthe solvent, and the residue is then heated at the same temperature.

[Preparation Process 20]

Compound (1) in which T¹ is a group —CO—CS—N(R′)—, in which R′ has thesame meaning as defined above can be prepared in accordance with thefollowing scheme:

wherein Q¹, Q², Q³, Q⁴, R¹, R² and R′ have the same meanings as definedabove, and T¹ represents a group —CO—CS—N(R′)—, in which R′ has the samemeaning as defined above.

More specifically, compound (9) may react with chloroacetyl chloride inthe presence of a base, giving compound (47). Compound (47) may beheated together with sodium thiosulfate in a solvent, giving sodiumthiosulfate derivative (48). The thus-obtained sodium thiosulfatederivative (48) may be heated with an amine, i.e., HN(R′)-Q⁴, givingcompound (1) according to the present invention.

As conditions, solvent and the like for preparing compound (47) fromcompound (9), may be applied those commonly used in reaction of an aminewith acid chloride. In order to prepare compound (48) from compound(47), it is only necessary to heat compound (47) together with sodiumthiosulfate under reflux for about 1 hour in a solvent such as ethanol.When compound (47) is a salt with hydrochloric acid or the like, thereaction may be performed in the presence of a base such as sodiumhydrogencarbonate. The preparation conditions of compound (48) are notlimited to those described herein, and the temperature and the kinds ofthe solvent and base may be suitably changed. The conditions for thereaction of compound (48) with HN(R′)-Q⁴ are the same as those describedin Preparation Process 19.

[Preparation Process 21]

Compound (1) in which T⁰ is a thiocarbonyl group (—CS—) can be preparedin accordance with the following scheme:

wherein Q¹, Q², Q³, Q⁴ and R² have the same meanings as defined above,and T¹ represents a group —SO₂—, —CO—, —CO—NH—, —CS—NH—, —CO—NH—NH—,—CO—CO—N(R′), in which R′ has the same meaning as defined above,—CO—CS—N(R′), in which R′ has the same meaning as defined above,—CS—CO—N(R′)—, in which R′ has the same meaning as defined above,—CS—CS—N(R′)—, in which R′ has the same meaning as defined above,—CO-A¹-N(R″)—, in which A¹ and R″ have the same meanings as definedabove, —CO-A²-CO—, in which A² has the same meaning as defined above,—CO-A³-CO—NH—, in which A³ has the same meanings as defined above, or—CO-A³-CO—, in which A³ has the same meaning as defined above.

More specifically, compound (49) may be subjected to dehydrationreaction with amine (50) in the presence of an acid catalyst such asp-toluenesulfonic acid, giving compound (51). Compound (51) may beheated together with sulfur powder in a solvent such as a mixed solventof methanol/methylene chloride, giving compound (1) according to thepresent invention. As conditions for preparing compound (51) fromcompound (49) and amine (50), may be applied those commonly used inpreparation of a Schiff base. Specifically, heating under reflux may beconducted in the presence of an acid catalyst in benzene or tolueneunder conditions that water is removed from the reaction system by, forexample, using a Dean-Stark trap. Molecular sieve may also be used inremoving water from the reaction system.

The important intermediates described in Preparation Process 1 to 21 ofthe compounds (1) according to the present invention will hereinafter bedescribed.

1) The compounds described in Preparation Process 1, 3 and 11 andrepresented by the following general formula (4):

HN(R¹)-Q³-N(R²)-T¹-Q⁴  (4)

wherein R¹, R², Q³ and Q⁴ have the same meanings as defined above, andT¹ represents a carbonyl group, sulfonyl group or group —CO—CO—N(R′), inwhich R′ has the same meaning as defined above, are important asintermediates for preparing compounds (1) according to the presentinvention.

Among the above-described intermediates, are preferred compounds inwhich T¹ is a group —C(═O)—C(═O)—N(R′), in which R′ means a hydrogenatom, hydroxyl group, alkyl group or alkoxy group, and compounds inwhich T¹ in the above formula is a carbonyl group, and Q³ is thefollowing group:

in which R³ and R⁴ have the same meanings as defined above, and Q⁵ meansa group —(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n areindependently of each other 0 or an integer of 1-3, and A means anoxygen atom, nitrogen atom, sulfur atom, —SO—, —SO₂—, —NH—, —O—NH—,—NH—NH—, —S—NH—, —SO—NH— or —SO₂—NH—.2) The compounds described in Preparation Process 2, 4 and 12 andrepresented by the following general formula (9):

Q¹-Q²-C(═O)—N(R¹)-Q³-NHR²  (9)

wherein R¹, R², Q¹, Q² and Q³ have the same meanings as defined above,are important as intermediates for preparing compounds (1) according tothe present invention.

Among the above-described intermediates, are preferred compounds inwhich Q³ is the following group:

in which R³ and R⁴ have the same meanings as defined above, and Q⁵ meansa group —(CH₂)_(n)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n areindependently of each other 0 or an integer of 1-3, and A means anoxygen atom, nitrogen atom, sulfur atom, —SO—, —SO₂—, —NH—, —O—NH—,—NH—NH—, —S—NH—, —SO—NH— or —SO₂—NH—.3) The following compounds (4C) described in Preparation Process 7, 11and 13 are important as intermediates for preparing compounds (1)according to the present invention.

wherein Q⁴, R³, R⁴, A, m and n have the same meanings as defined above,and T¹ represents a carbonyl group, sulfonyl group or group—CO—CO—N(R′), in which R′ has the same meaning as defined above.

Among the above-described intermediates, are preferred compounds inwhich T¹ in the above formula is a group —CO—CO—N(R′), in which R′ hasthe same meaning as defined above, and compounds in which T¹ is acarbonyl group, and A is an oxygen atom, nitrogen atom, sulfur atom,—SO—, —SO₂—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO₂—NH—.

4) The following compounds (22) described in Preparation Process 8 and13 are important as intermediates for preparing compounds (1) accordingto the present invention.

wherein Q⁴, R³, R⁴, A, m and n have the same meanings as defined above,T¹ represents a carbonyl group, sulfonyl group or group —CO—CO—N(R′), inwhich R′ has the same meaning as defined above, and R⁵¹ represents aprotecting group for amino group.

Among the above-described intermediates, are preferred compounds inwhich T¹ in the above formula is a group —CO—CO—N(R′), in which R′ hasthe same meaning as defined above, and compounds in which T¹ is acarbonyl group, and A is an oxygen atom, nitrogen atom, sulfur atom,—SO—, —SO₂—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO₂—NH—.

5) The following optically active compounds (7a) described inPreparation Process 6 are important as intermediates for preparingcompounds (1) according to the present invention.

wherein Q⁵, R¹, R², R³ and R⁴ have the same meanings as defined above,and R⁵⁰ represents a protecting group for amino group.

Among the above-described intermediates, are preferred compounds inwhich Q⁵ in the above formula is a group—(CH₂)_(m)—CH₂-A-CH₂—(CH₂)_(n)—, in which m and n are independently ofeach other 0 or an integer of 1-3, and A means an oxygen atom, nitrogenatom, sulfur atom, —SO—, —SO₂—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH—or —SO₂—NH—.

6) The following compounds (21) described in Preparation Process 8 areimportant as intermediates for preparing compounds (1) according to thepresent invention.

wherein R³, R⁴, A, m and n have the same meanings as defined above, andR⁵¹ represents a protecting group for amino group.

Among the above-described intermediates, are preferred compounds inwhich A in the above formula is an oxygen atom, nitrogen atom, sulfuratom, —SO—, —SO₂—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO₂—NH—.

7) The following compounds described in Preparation Process 10 areimportant as intermediates for preparing compounds (1) according to thepresent invention. More specifically, the following optically activetrans-form compounds (30), (31) and (32):

wherein R³, m and n have the same meanings as defined above, and R⁵¹ andR⁶¹ represent protecting groups for amino group, enantiomers (30a),(31a) and (32a) of the above compounds prepared in a similar manner:

wherein R³, m and n have the same meanings as defined above, and R⁵¹ andR⁶¹ represent protecting groups for amino group, cis-form compounds(30b), (31b) and (32b):

wherein R³, m and n have the same meanings as defined above, and R⁵¹ andR⁶¹ represent protecting groups for amino group, and enantiomers (30c),(31c) and (32c) thereof:

wherein R³, m and n have the same meanings as defined above, and R⁵¹ andR⁶¹ represent protecting groups for amino group, are important asintermediates for preparing compounds (1) according to the presentinvention.

The cyclic diamine derivatives according to the present inventionexhibit strong inhibitory effects on activated blood coagulation factorX and are thus useful for medicines for mammal including human,anticoagulants factor X, agents for preventing and/or treatingthrombosis or embolism, agents for preventing and/or treating thrombticdiseases, and agents for preventing and/or treating cerebral infarction,cerebral embolism, myocardial infarction, angina pectoris, pulmonaryinfarction, pulmonary embolism, Buerger's disease, deep venousthrombosis, disseminated intravascular coagulation syndrome, thrombusformation after valve or joint replacement, thrombus formation andreocclusion after angioplasty, systemic inflammatory reaction syndrome(SIRS), multiple organ disease syndrome (MODS), thrombus formationduring extracorporeal circulation, or blood clotting upon bloodgathering.

When a compound according to the present invention is used as a medicinefor human body, the dose is within a range of 1 mg to 1 g, preferably 10to 300 mg, per day for an adult. The dose for animal varies according tothe object (treatment or prevention) of the administration, the kind andsize of an animal to be treated, the kind of a contagium, and thecondition of a disease attacked. However, it is generally within a rangeof 0.1 to 200 mg, preferably 0.5 to 100 mg, per kg of weight a day.Meanwhile, the administration may be once per day, or may be dividedinto 2 to 4 times per day. The dose per day may exceed the above rangeif necessary.

Medicinal compositions comprising the compound according to the presentinvention can be prepared by selecting a suitable preparation formaccording to an administration method in accordance with a preparationmethod for the preparation form used. As examples of the preparationforms of the medicinal compositions comprising the compound according tothe present invention as a main component, may be mentioned tablets,tablets, powder, granules, capsules, solutions, syrups, elixirs, oil oraqueous suspensions or the like for oral preparations.

In the case of an injection, a stabilizer, a preservative and adissolution aid may be used in a preparation. A solution which maycontain these auxiliaries in some cases may also be provided as a solidform for preparing upon use by containing the solution into a containerand then drying the solution by lyophilization or the like. A dose ordoses of the injection may also be contained into a container.

As example of preparation forms for external application, may bementions solutions, suspensions, emulsions, ointments, gel, creams,lotions, sprays, plasters or the like.

A solid preparation may contain pharmaceutically acceptable additives inaddition to the compound according to the present invention. Forexample, fillers, extenders, binders, disintegrators, dissolutionaccelerators, wetting agents, etc. may be suitably selected and mixed,giving a preparation.

As example of preparation forms of a liquid preparation, may bementioned solutions, suspensions, emulsions and the like. They maycontain a suspending agent, emulsifier and/or the like in some cases.

EXAMPLES

However, the present invention is not limited to these examples.

Referential Example 1 tert-Butyl pyridin-4-ylcarbamate

4-Aminopyridine (10 g) was dissolved in tetrahydrofuran (500 ml),di-tert-butyl dicarbonate (25.5 g) was added to the solution, and themixture was stirred at room temperature for 10 minutes. The resultantreaction mixture was concentrated under reduced pressure, and depositedsolids were washed with hexane to obtain the title compound (16.9 g).

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 6.86 (1H, br.s), 7.30 (2H, dd, J=1.5,4.9 Hz), 8.44 (2H, dd, J=1.5, 4.9 Hz).

MS (FAB) m/z: 195 (M+H)⁺.

Referential Example 2 tert-Butyl 3-sulfanylpyridin-4-ylcarbamate

The compound (61.6 g) obtained in Referential Example 1 was dissolved intetrahydrofuran (2,000 ml), and the solution was stirred at −78° C. for10 minutes. A hexane solution (1.59 mol/l, 500 ml) of n-butyllithium wasadded dropwise to the solution, and the mixture was stirred for 10minutes and then for 2 hours with ice cooling. After the reactionmixture was cooled to −78° C., sulfur powder (12.2 g) was added, and theresultant mixture was warmed to room temperature and stirred for 1 hour.Water (1,000 ml) was added to the reaction mixture to separate a waterlayer. After 3N hydrochloric acid was added to the water layer to adjustthe pH of the water layer to 3 to 4, methylene chloride was added toseparate an organic layer. The organic layer was dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (methylene chloride:methanol=50:1) to obtain the title compound(33.2 g).

¹H-NMR (DMSO-d₆) δ: 1.52 (9H, s), 7.89 (1H, d, J=6.4 Hz), 7.99 (1H, d,J=6.4 Hz), 8.20 (1H, s), 9.91 (1H, br.s).

MS (FAB) m/z: 227 (M+H)⁺.

Referential Example 3 Thiazolo[5,4-c]pyridine

The compound (33.2 g) obtained in Referential Example 2 was dissolved informic acid (250 ml), and the solution was heated under reflux for 3days. The reaction mixture was concentrated under reduced pressure, anda 5N aqueous solution (100 ml) of potassium hydroxide and diethyl etherwere added to the residue to separate an organic layer. The organiclayer was dried over anhydrous sodium sulfate, and the solvent was thendistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel (methylene chloride:methanol=25:1) toobtain the title compound (9.03 g).

¹H-NMR (CDCl₃) δ: 8.05 (1H, d, J=5.4 Hz), 8.70 (1H, d, J=5.4 Hz), 9.23(1H, s), 9.34 (1H, s).

MS (FAB) m/z: 137 (M+H)⁺.

Referential Example 4 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

The compound (1.61 g) obtained in Referential Example 3 was dissolved inN,N-dimethylformamide (50 ml), and to the solution methyl iodide (1.50ml) was added, the resultant mixture was stirred at 80° C. for 4 hours.The reaction mixture was concentrated under reduced pressure, and theresidue was dissolved in methanol (100 ml), sodium borohydride (1.53 g)was added, and the resultant mixture was stirred at room temperature for1 hour. The reaction mixture was concentrated under reduced pressure,and a saturated aqueous solution of potassium carbonate and diethylether were added to the residue to separate an organic layer. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas distilled off under reduced pressure. The residue was purified bycolumn chromatography on silica gel (methylene chloride:methanol=25:1)to obtain the title compound (1.28 g).

¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.83 (2H, t, J=5.9 Hz), 2.98 (2H, t,J=5.9 Hz), 3.70 (2H, s), 8.63 (1H, s).

MS (FAB) m/z: 155 (M+H)⁺.

Referential Example 5 Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The compound (6.43 g) obtained in Referential Example 4 was dissolved inabsolute tetrahydrofuran (200 ml), to the solution n-butyllithium (1.47Nhexane solution, 34.0 ml) was added dropwise at −78° C., and theresultant mixture was stirred for 40 minutes. After carbon dioxide gaswas blown into the reaction mixture at −78° C. for 1 hour, the reactionmixture was warmed to room temperature and then concentrated underreduced pressure to obtain the title compound (9.42 g).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.64-2.77 (4H, m), 3.54 (2H, s).

MS (FAB) m/z: 199 (M+H)⁺.

Referential Example 6 tert-Butyl2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5[4H]-carboxylate

1-tert-Butoxycarbonyl-4-piperidone (40.0 g) was dissolved in cyclohexane(80 ml), and to the solution p-toluenesulfonic acid monohydrate (191 mg)and pyrrolidine (17.6 ml) were added. The mixture was heated underreflux for 2 hours while removing water using a Dean-Stark trap. Afterthe reaction mixture was concentrated under reduced pressure, theresidue was dissolved in methanol (60 ml), and sulfur powder (6.42 g)was added. A methanol solution (10 ml) of cyanamide (8.44 g) was slowlyadded dropwise to the solution with ice cooling, and the mixture wasstirred at room temperature for 5 hours. Precipitated solid materialswere collected by filtration to obtain the title compound (31.0 g).

¹H-NMR (DMSO-d₆) δ: 1.41 (9H, s), 2.44 (2H, t, J=5.6 Hz), 3.57 (2H, t,J=5.6 Hz), 4.29 (2H, s), 6.79 (2H, s).

MS (EI) m/z: 255 (M⁺).

Referential Example 7 tert-Butyl2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5[4H]-carboxylate

Copper(II) bromide (1.05 g) was suspended in N,N-dimethylformamide (20ml), and tert-butyl nitrite (0.696 ml) and the compound (1.00 g)obtained in Referential Example 6 were added with ice cooling, thereaction mixture was heated and stirred at 40° C. for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:5) to obtain the title compound (568 mg).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.85 (2H, br.s), 3.72 (2H, br.s), 4.56(2H, br.s).

MS (FAB) m/z: 319 (M+H)⁺.

Referential Example 8 2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinetrifluoroacetate

The compound (890 mg) obtained in Referential Example 7 was dissolved inmethylene chloride (2 ml), and to the solution trifluoroacetic acid (15ml) was added, and the mixture was stirred at room temperature for 30seconds. The reaction mixture was concentrated under reduced pressure,and diethyl ether was added to the residue. Precipitated solid materialswere collected by filtration to obtain the title compound (867 mg).

¹H-NMR (DMSO-d₆) δ: 2.98 (2H, t, J=6.1 Hz), 3.45 (2H, t, J=6.1 Hz), 4.35(2H, s), 9.53 (2H, br.s).

MS (FAB) m/z: 219 (M+H)⁺.

Referential Example 92-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

The compound (422 mg) obtained in Referential Example 8 was suspended inmethylene chloride (10 ml), and triethylamine (0.356 ml) was added tomake a solution. Acetic acid (0.216 ml), an aqueous solution (35%solution, 0.202 ml) of formaldehyde and sodium triacetoxyborohydride(428 mg) were successively added to the solution, and the resultantmixture was stirred at room temperature for 1 hour. A saturated aqueoussolution (100 ml) of sodium hydrogencarbonate, methylene chloride (100ml) and a 3N aqueous solution (3 ml) of sodium hydroxide were added tothe reaction mixture to conduct liquid separation. After an organiclayer was dried over anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure. The residue was purified by columnchromatography on silica gel (methylene chloride:methanol=100:3) toobtain the title compound (286 mg).

¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 2.79 (2H, t, J=5.7 Hz), 2.85-2.93 (2H,m), 3.58 (2H, t, J=1.8 Hz).

MS (FAB) m/z: 233 (M+H)⁺.

Referential Example 10 Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The compound (531 mg) obtained in Referential Example 9 was dissolved inabsolute diethyl ether (20 ml), n-butyllithium (1.54N hexane solution,1.63 ml) was added dropwise at −78° C., and the mixture was stirred for30 minutes with ice cooling. After passing carbon dioxide into thereaction mixture at −78° C. for 10 minutes, the mixture was warmed toroom temperature. The reaction mixture was concentrated under reducedpressure to obtain the title compound (523 mg).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.64-2.85 (4H, m), 3.54 (2H, s).

Referential Example 11 Ethyl2-[(E)-2-phenylethenyl]oxazole-4-carboxylate

Synthesis was conducted in accordance with the report (J. Org. Chem.,1996, Vol. 61, p. 6496) by Panek et al. Sodium hydrogencarbonate (22.8g) and ethyl bromopyruvate (10.5 ml) were added to a solution ofcinnamamide (10.0 g) in tetrahydrofuran (250 ml) at room temperature,and the mixture was heated under reflux for 48 hours. The reactionmixture was allowed to cool to room temperature, filtered through Celiteand then concentrated under reduced pressure to obtain residue.Trifluoroacetic anhydride (30 ml) was added to a solution of thisresidue in tetrahydrofuran (30 ml) at 0° C., and the mixture wasgradually warmed to room temperature. After the mixture was stirred for63 hours, a saturated aqueous solution (500 ml) of sodiumhydrogencarbonate and ethyl acetate (150 ml) were added to the reactionmixture, and a water layer was separated. The water layer was extractedwith ethyl acetate (150 ml). The organic layers were combined, washedwith saturated aqueous solution of sodium chloride (150 ml), dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=5:1→3:1) to obtain the title compound (10.9 g).

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.0 Hz), 4.42 (2H, q, J=7.0 Hz), 6.96(1H, d, J=16.6 Hz), 7.30-7.40 (3H, m), 7.53 (2H, d, J=6.8 Hz), 7.63 (1H,d, J=16.6 Hz), 8.20 (1H, s).

Referential Example 12 2-[(E)-2-phenylethenyl]oxazole-4-carbaldehyde

Diisobutylaluminum hydride (1.0N hexane solution, 66 ml) was addeddropwise to a solution of the compound (8.57 g) obtained in ReferentialExample 11 in methylene chloride (80 ml) at −78° C. After 15 minutes,methanol (11 ml) was added dropwise, and the mixture was warmed to roomtemperature over 1 hour. The reaction mixture was filtered throughCelite, and the resultant pasty substance was dissolved in ethyl acetate(200 ml) and a saturated aqueous solution (200 ml) of ammonium chloridewas added, and a water layer was separated. The water layer was thenextracted with methylene chloride (2×100 ml). The resultant organiclayers were collected and washed with a saturated aqueous solution (100ml) of sodium hydrogencarbonate and saturated aqueous solution of sodiumchloride (100 ml), combined with the filtrate obtained by the filtrationthrough Celite and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by column chromatography on silica gel (methylenechloride:ethyl acetate=5:1→methylene chloride:methanol=10:1) to obtainthe title compound (5.86 g).

¹H-NMR (CDCl₃) δ: 6.96 (1H, d, J=16.6 Hz), 7.35-7.45 (3H, m), 7.56 (2H,d, J=6.4 Hz), 7.67 (1H, d, J=16.6 Hz), 8.26 (1H, s), 9.98 (1H, s).

MS (FAB) m/z: 200 (M+H)⁺.

Referential Example 13 2-[(E)-2-Phenylethenyl]-4-vinyloxazole

n-Butyllithium (1.54N hexane solution, 14.2 ml) was added dropwise to asolution of methyltriphenylphosphonium bromide (8.16 g) intetrahydrofuran (80 ml) at 0° C., and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was cooled again to 0°C., a solution of the compound (3.64 g) obtained in Referential Example12 in tetrahydrofuran (20 ml) was added, and the mixture was warmed toroom temperature. After stirring for 2 hours, water (200 ml) and ethylacetate (100 ml) were added and a water layer was separated. The waterlayer was extracted with ethyl acetate (50 ml). After the organic layerswere combined, washed with saturated aqueous solution of sodium chloride(100 ml) and dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=4:1→3:1) to obtainthe title compound (2.84 g).

¹H-NMR (CDCl₃) δ: 5.33 (1H, dd, J=1.5, 10.7 Hz), 5.98 (1H, dd, J=1.5,17.6 Hz), 6.56 (1H, dd, J=10.7, 17.6 Hz), 6.95 (1H, d, J=16.6 Hz),7.31-7.42 (3H, m), 7.49-7.56 (4H, m).

MS (FAB) m/z: 198 (M+H)⁺.

Referential Example 14 2-{2-[(E)-2-Phenylethenyl]oxazol-4-yl}-1-ethanol

9-Borabicyclo[3.3.1]nonane (0.5N tetrahydrofuran solution, 158 ml) wasadded to a solution of the compound (13.0 g) obtained in ReferentialExample 13 in tetrahydrofuran (500 ml), and the mixture was stirred atroom temperature for 15 hours. Water (10 ml), a 3N aqueous solution (80ml) of sodium hydroxide and aqueous hydrogen peroxide (80 ml) weresuccessively added dropwise to the reaction mixture at 0° C., and themixture was stirred at room temperature for 6 hours. After water (600ml) and ethyl acetate (200 ml) were added to the resultant reactionmixture to separate a water layer, the water layer was extracted withethyl acetate (200 ml). After the organic layers were collected, washedwith saturated aqueous solution of sodium chloride (200 ml) and driedover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=2:1→ethyl acetate alone) to obtain thetitle compound (14.1 g).

¹H-NMR (CDCl₃) δ: 2.69 (1H, br.s), 2.80 (2H, t, J=5.6 Hz), 3.90-3.97(2H, m), 6.91 (1H, d, J=16.6 Hz), 7.30-7.42 (4H, m), 7.43-7.56 (3H, m).

MS (FAB) m/z: 216 (M+H)⁺.

Referential Example 152-(2-{2-[(E)-2-Phenylethenyl]oxazol-4-yl}ethyl)-1H-isoindol-1,3(2H)-dione

Phthalimide (200 mg), triphenylphosphine (357 mg) and diethylazodicarboxylate (0.214 ml) were added to a solution of the compound(292 mg) obtained in Referential Example 14 in tetrahydrofuran (15 ml)at room temperature, and the mixture was stirred for 4 hours. Thesolvent of the reaction mixture was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (hexane:ethyl acetate=3:1) to obtain the title compound (447 mg).

¹H-NMR (CDCl₃) δ: 2.98 (2H, t, J=7.2 Hz), 4.03 (2H, t, J=7.2 Hz), 6.88(1H, d, J=16.6 Hz), 7.28-7.45 (5H, m), 7.48 (2H, d, J=7.3 Hz), 7.71 (2H,dd, J=2.9, 5.4 Hz), 7.84 (2H, dd, J=2.9, 5.4 Hz).

MS (FAB) m/z: 345 (M+H)⁺.

Referential Example 16 tert-Buthyl2-{2-[(E)-2-phenylethenyl]oxazol-4-yl}ethylcarbamate

After hydrazine monohydrate (1.50 ml) was added to a solution of thecompound (6.40 g) obtained in Referential Example 15 in ethanol (150 ml)at room temperature, and the mixture was stirred for 1 hour, hydrazinemonohydrate (0.500 ml) was added again at room temperature, and themixture was stirred for 2 hours. Methylene chloride (150 ml), asaturated aqueous solution (150 ml) of sodium hydrogencarbonate anddi-tert-butyl dicarbonate (13.4 g) were added to the reaction mixture atroom temperature. After stirring for 30 minutes, a water layer wasseparated and extracted with methylene chloride (50 ml). The resultantorganic layers were combined and dried over anhydrous sodium sulfate,and the solvent was then distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1→1:1) to obtain the title compound (5.06 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.75 (2H, t, J=6.6 Hz), 3.46 (2H, dt,J=5.9, 6.6 Hz), 4.92 (1H, br.s), 6.91 (1H, d, J=16.6 Hz), 7.29-7.45 (4H,m), 7.48 (1H, d, J=16.6 Hz), 7.52 (2H, d, J=7.3 Hz).

MS (FAB) m/z: 315 (M+H)⁺, 259 (M-isobutene+H)⁺, 315 (M-Boc+H)⁺.

Referential Example 17 tert-Buthyl2-[(E)-2-phenylethenyl]-6,7-dihydrooxazolo-[5,4-c]pyridine-5(4H)-carboxylate

Paraformaldehyde (54.5 mg) and p-toluenesulfonic acid (7.2 mg) wereadded to a solution of the compound (190 mg) obtained in ReferentialExample 16 in toluene (15 ml) at room temperature. After heating underreflux for 1 hour, the reaction mixture was allowed to cool, and ethylacetate (15 ml) and a saturated aqueous solution (15 ml) of sodiumhydrogencarbonate were added to the reaction mixture to separate a waterlayer. After the water layer was extracted with ethyl acetate (10 ml),the resultant organic layers were combined and dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (hexane:ethyl acetate=3:1→2:1) to obtain the title compound (153mg).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.67 (2H, br.s), 3.73 (2H, br.s), 4.55(2H, s), 6.90 (1H, d, J=16.1 Hz), 7.29-7.42 (3H, m), 7.46 (1H, d, J=16.1Hz), 7.52 (2H, d, J=7.3 Hz).

MS (FAB) m/z: 327 (M+H)⁺, 271 (M-isobutene+H)⁺, 227 (M-Boc+H)⁺.

Referential Example 18 tert-Butyl2-formyl-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate

Acetone (8.0 ml), water (4.0 ml), N-methylmorpholine N-oxide (577 mg)and a 0.039 M aqueous solution (3.20 ml) of osmium tetroxide were addedto a solution of the compound (803 mg) obtained in Referential Example17 in tetrahydrofuran (16 ml) at room temperature, and the mixture wasstirred overnight. Ethyl acetate (50 ml) and a 10% aqueous solution (50ml) of sodium thiosulfate were added to the reaction mixture to separatea water layer. The water layer was then extracted with ethyl acetate (30ml). After the resultant organic layers were combined and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure. Methanol (8.0 ml), water (8.0 ml) and sodium metaperiodate(790 mg) were added to a solution of the residue in tetrahydrofuran (16ml). After stirring for 3 hours, ethyl acetate (30 ml) and water (50 ml)were added to the reaction mixture to separate a water layer. The waterlayer was extracted with ethyl acetate (20 ml). After the resultantorganic layers were combined, washed with a saturated solution (50 ml)of sodium hydrogencarbonate and dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=4:1→2:1) to obtain the title compound (234 mg). Since thisaldehyde was unstable, it was immediately used in the next reaction.

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.77 (2H, br.s), 3.77 (2H, br.s), 4.62(2H, s), 9.70 (1H, s).

Referential Example 19 5-(tert-Butyl) 2-methyl6,7-dihydrooxazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate

Sodium cyanide (220 mg) and manganese dioxide (780 mg) were added to asolution of the compound (225 mg) obtained in Referential Example 18 inmethanol (9.0 ml) at room temperature. After stirring for 30 minutes,the reaction mixture was filtered through Celite with ethyl acetate. Thefiltrate was washed with water (50 ml) and saturated aqueous solution ofsodium chloride (50 ml) and dried over anhydrous sodium sulfate. Thesolvent was then distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel (hexane:ethylacetate=3:2→1:1) to obtain the title compound (120 mg).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.73 (2H, br.s), 3.74 (2H, br.s), 4.01(3H, s), 4.59 (2H, s).

MS (FAB) m/z: 283 (M+H)⁺.

Referential Example 20 Methyl5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine-2-carboxylate

Trifluoroacetic acid (15 ml) was added to a solution of the compound(500 mg) obtained in Referential Example 19 in methylene chloride (15ml) at room temperature, and the mixture was stirred for 10 minutes. Thereaction mixture was concentrated under reduced pressure, and methylenechloride (20 ml), triethylamine (0.495 ml), acetic acid (205 ml),formalin (0.230 ml) and sodium triacetoxyborohydride (570 mg) were addedto the resultant residue at room temperature. After stirring for 15minutes, methylene chloride (20 ml) and a saturated aqueous solution (50ml) of sodium hydrogencarbonate were added to separate an organic layer.The water layer was extracted with methylene chloride (3×20 ml). Afterthe resultant organic layers were combined and dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The residue was purified by column chromatography on silica gel(chloroform:methanol=20:1→10:1) to obtain the title compound (257 mg).

¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.72-2.78 (2H, m), 2.78-2.83 (2H, m),3.61 (2H, t, J=1.7 Hz), 4.00 (3H, s).

MS (FAB) m/z: 197 (M+H)⁺, 165 (M-OCH₃)⁺.

Referential Example 21 Lithium5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine-2-carboxylate

Water (6.0 ml) and lithium hydroxide (99.7 mg) were added to a solutionof (800 mg) obtained in Referential Example 20 in tetrahydrofuran (24ml) at room temperature, and the mixture was stirred for 10 minutes. Thereaction mixture was concentrated under reduced pressure to obtain thetitle compound (825 mg).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.47 (2H, t, J=5.6 Hz), 2.64 (2H, t,J=5.6 Hz), 3.43 (2H, s).

Referential Example 22 Methyl 5-chloro-6-fluoroindole-2-carboxylate

A mixture of methyl 3-chloro-4-fluoro-α-azidocinnamate (Japanese PatentApplication Laid-Open No. 149723/1995) (1.85 g) and xylene (140 ml) washeated under reflux for 1 hour, and the solvent was then distilled off.The residue was purified by column chromatography on silica gel(methylene chloride) to obtain the title compound (491 mg).

¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 7.13-7.15 (1H, m), 7.20 (1H, dd, J=9.3,0.49 Hz), 7.71 (1H, d, J=7.3 Hz), 8.93 (1H, br.s).

MS (FAB) m/z: 227 M⁺.

Referential Example 23 5-Chloro-6-fluoroindole-2-carboxylic acid

The compound (461 mg) obtained in Referential Example 22 was dissolvedin a mixed solvent of tetrahydrofuran (15 ml), methanol (10 ml) andwater (10 ml), lithium hydroxide (283 mg) was added at room temperature,and the mixture was stirred for 4 hours. The solvent was distilled offunder reduced pressure, and 1N hydrochloric acid was added to theresidue to weakly acidify it. The resultant powder was collected byfiltration and dried to obtain the title compound (422 mg).

¹H-NMR (CDCl₃) δ: 7.08-7.10 (1H, m), 7.34 (1H, d, J=9.5 Hz), 7.88 (1H,d, J=7.6 Hz), 12.04 (1H, s), 13.16 (1H, s).

MS (FAB) m/z: 213 (M⁺).

Referential Example 245-(Pyridin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

1) Diphosphorus pentasulfide (500 g) was suspended in formamide (3,000ml) with ice cooling, and the suspension was stirred overnight. Waterand diethyl ether were added to the reaction mixture, and an organiclayer was separated and dried over anhydrous magnesium sulfate, and thesolvent was distilled off to obtain an oil. After the oil was dissolvedin n-butanol (350 ml), and ethyl 3-chloro-4-oxo-1-piperidinecarboxylate(150 g) synthesized according to the process described in literature(Tetrahedron, 1983, Vol. 39, p. 3767) was added to the solution, theresultant mixture was stirred at 100° C. for 2.5 hours. The reactionmixture was filtered through Celite. The filtrate was washed with asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride, and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methylene chloride→ethyl acetate:hexane=1:2) to obtain ethyl6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (79.0 g).

¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.3 Hz), 2.96 (2H, br.s), 3.82 (2H,br.s), 4.19 (2H, +, J=7.3 Hz), 4.73 (2H, br.s), 8.68 (1H, s).

MS (FAB) m/z: 213 (M+H)⁺.

2) A 3.5N aqueous solution (250 ml) of sodium hydroxide was added to thereaction product (33.5 g) obtained above, and the mixture was heatedunder reflux overnight. After the reaction mixture was cooled to roomtemperature, di-tert-butyl dicarbonate (103 g) was added with icecooling, and the mixture was stirred overnight at room temperature.After 3N hydrochloric acid was added to the reaction mixture to adjustthe pH thereof to 1 to 2, methylene chloride was added. After separationof an organic layer, the organic layer was washed successively with anaqueous solution of sodium hydrogencarbonate and saturated aqueoussolution of sodium chloride and then dried over anhydrous sodiumsulfate. After the organic layer was concentrated under reducedpressure, the resultant residue was purified by column chromatography onsilica gel (ethyl acetate:hexane=1:2) to obtain tert-butyl6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (21.1 g).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.94 (2H, br.s), 3.76 (2H, br.s), 4.68(2H, s), 8.67 (1H, s).

MS (FAB) m/z: 241 (M+H)⁺.

3) Trifluoroacetic acid (25 ml) was added to a solution of the compound(5.00 g) obtained in the step 2) in methylene chloride (25 ml) at roomtemperature. After stirring for 10 minutes, the reaction mixture wasconcentrated under reduced pressure, and 4-bromopyridine (5.20 g),N,N-dimethylformamide (30 ml) and triethylamine (15.5 ml) were added tothe residue at room temperature, and the mixture was stirred at 150° C.for 2 days and then allowed to cool to room temperature. Colorlessprecipitates were separated by filtration, and the filtrate wasconcentrated under reduced pressure. Thereafter, methylene chloride (50ml) and a saturated aqueous solution (100 ml) of sodiumhydrogencarbonate were added, and the resultant water layer wassaturated with sodium chloride. After separation of an organic layer,the resultant water layer was extracted with methylene chloride (5×30ml). After the resultant organic layers were combined and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (methylene chloride:methanol=20:1→8:1) to obtain the title compound(2.97 g).

¹H-NMR (CDCl₃) δ: 3.07 (2H, t, J=5.9 Hz), 3.81 (2H, t, J=5.9 Hz), 4.61(2H, s), 6.74 (2H, t, J=6.5 Hz), 8.30 (2H, t, J=6.5 Hz), 8.70 (1H, s).

MS (ESI) m/z: 218 (M+H)⁺.

Referential Example 25 2-Chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole

1) Tetrahydro-4H-pyran-4-one (5.0 g) was dissolved in cyclohexane (20ml), pyrrolidine (4.35 ml) and p-toluenesulfonic acid monohydrate (48mg) were added, and the mixture was heated under reflux for 70 minuteswhile removing water by a Dean-Stark trap. The reaction mixture wascooled to room temperature, and a supernatant was taken out andconcentrated under reduced pressure. The residue was dissolved inmethanol (15 ml), and sulfur powder (1.60 g) was added with ice cooling.After 15 minutes, a methanol solution (10 ml) of cyanamide (2.10 g) wasadded dropwise over 20 minutes, and the mixture was stirred for 3 days.The solvent was distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel (methylenechloride:methanol=20:1→10:1→4:1) to obtain6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-ylamine (3.97 g).

¹H-NMR (CDCl₃) δ: 2.66-2.70 (2H, m), 3.97 (2H, t, J=5.6 Hz), 4.63 (2H,s), 4.94 (2H, br.s).

MS (FAB) m/z: 157 (M+H)⁺.

2) Copper(II) chloride (4.10 g) was dissolved in acetonitrile (50 ml),and tert-butyl nitrite (3.93 g) was added in one portion with icecooling. After 10 minutes, the compound obtained in the above-describedreaction (3.97 g) was added over about 1 hour, and the reaction mixturewas stirred at room temperature for 1 hour. The reaction mixture washeated to 65° C. and continuously stirred for 2 hours. After silica gel(20 g) was added to the reaction mixture, the solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=3:1) to obtain thetitle compound (1.78 g).

¹H-NMR (CDCl₃) δ: 2.85-2.89 (2H, m), 4.02 (2H, t, J=5.6 Hz), 4.73 (2H,s).

MS (FAB) m/z: 175 (M+H)⁺.

Referential Example 26 Lithium6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-carboxylate

1) The compound (1.78 g) obtained in Referential Example 25 wasdissolved in methanol (30 ml), and to the solution 10% palladium oncarbon (300 mg) and sodium acetate (830 mg) were added. The mixture wasstirred for 5 days in a hydrogen stream of 5 atm. After the catalyst wasseparated by filtration, the solvent was concentrated, and the residuewas subjected to column chromatography on silica gel (hexane:ethylacetate=2:1) to obtain 6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.14 g).

¹H-NMR (CDCl₃) δ: 2.97-3.01 (2H, m), 4.04 (2H, t, J=5.6 Hz), 4.87 (2H,s), 8.69 (1H, s).

MS (FAB) m/z: 142 (M+H)⁺.

2) After the product (1.14 g) obtained above was dissolved in diethylether (30 ml) and cooled to −78° C., 1.6 M butyllithium (6.6 ml) wasadded, and the mixture was stirred. After 20 minutes, bubbling wasconducted with carbon dioxide for 15 minutes. The reaction mixture waswarmed to room temperature and concentrated under reduced pressure toobtain the title compound (1.65 g).

¹H-NMR (DMSO-d₆) δ: 2.83 (2H, t, J=5.6 Hz), 3.92 (2H, t, J=5.6 Hz), 4.73(2H, s).

Referential Example 27 Thiazolo[4,5-c]pyridine

3-(tert-Butoxycarbonylamino)-4-mercaptopyridine (Japanese PatentApplication Laid-Open No. 321691/1992) (9.20 g) was dissolved in formicacid (60 ml) and heated under reflux for 4 hours. The reaction mixturewas concentrated under reduced pressure, and a 5N aqueous solution (100ml) of potassium hydroxide and diethyl ether were added to the residueto conduct liquid separation. The resultant organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. Diethyl ether was added to the residue, and solidsdeposited were collected by filtration to obtain the title compound(3.97 g).

¹H-NMR (CDCl₃) δ: 7.93 (1H, d, J=5.4 Hz), 8.60 (1H, d, J=5.4 Hz), 9.07(1H, s), 9.46 (1H, s).

Referential Example 285-Methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine

The title compound was obtained from the compound obtained inReferential Example 27 in a similar manner to Referential Example 4.

¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.77 (2H, t, J=5.4 Hz), 2.92-3.00 (2H,m), 3.69 (2H, t, J=2.0 Hz), 8.61 (1H, s).

MS (FAB) m/z: 155 (M+H)⁺.

Referential Example 29 Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 28 in a similar manner to Referential Example 5.

¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 2.64 (2H, br.s), 2.80 (2H, br.s), 3.44(2H, br.s).

Referential Example 302-Chloro-N,N-dimethyl-4,5,6,7-tetrahydrobenzothiazole-6-amine

2-Chloro-4,7-dihydro-1,3-benzothiazol-6(5H)-one (Helv. Cim. Acta., 1994,Vol. 77, p. 1256) (2.0 g) was dissolved in methanol (100 ml), andammonium acetate (8.2 g) and sodium cyanoborohydride (4.0 g) were addedto heat the mixture under reflux for 20 hours. Hydrochloric acid wasadded to the reaction mixture to decompose excessive sodiumcyanoborohydride before the solvent was distilled off under reducedpressure. The residue was alkalified with a 1N solution of sodiumhydroxide and then extracted with methylene chloride. The resultantorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain a pale yellowoil. This oil was dissolved in methanol (50 ml), and an aqueous solution(4.29 g) of formaldehyde and sodium cyanoborohydride (3.49 g) were addedto stir the mixture at room temperature for 12 hours. The solvent wasdistilled off under reduced pressure, and methylene chloride was addedto the residue, the organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=10:1) to obtain the title compound (740 mg).

¹H-NMR (CDCl₃) δ: 1.71-1.78 (1H, m), 2.10-2.19 (1H, m), 2.35 (6H, s),2.66-2.94 (5H, m).

MS (FAB) m/z: 217 (M+H)⁺.

Referential Example 31 Lithium6-(dimethylamino)-4,5,6,7-tetrahydrobenzothiazole-2-carboxylate

After the compound (750 mg) obtained in Referential Example 30 wasdissolved in diethyl ether (15 ml), and the solution was cooled to −78°C., 1.5N t-butyllithium (3.5 ml) was added, the mixture was stirred for20 minutes, and carbon dioxide was then bubbled for about 15 minutes.The reaction mixture was warmed to room temperature and concentratedunder reduced pressure to obtain the title compound.

¹H-NMR (DMSO-d₆) δ: 1.75-1.78 (1H, m), 1.98-2.07 (1H, m), 2.50 (6H, s),2.64-2.88 (5H, m).

Referential Example 32 tert-Butyl2-amino-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate

1-tert-Butoxycarbonyl-3-pyrrolidone (1.58 g) was dissolved incyclohexane (10 ml), p-toluenesulfonic acid monohydrate (8.12 mg) andpyrrolidine (607 mg) were added, and the mixture was heated under refluxfor 1.5 hours while dewatering with a Dean-Stark trap. After asupernatant was taken out and concentrated under reduced pressure, theresidue was dissolved in methanol (5 ml), and sulfur powder (274 mg) wasadded. The mixture was stirred for 15 minutes under ice cooling. Amethanol solution (2 ml) of cyanamide (377 mg) was slowly added dropwiseto the reaction mixture, and the mixture was stirred overnight at roomtemperature. The mixture was additionally heated under reflux for 2hours, the reaction mixture was concentrated, and methylene chloride anda saturated aqueous solution of sodium hydrogen carbonate were added.The resultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methanol:methylenechloride=1:39) to obtain the title compound (248 mg).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 4.34-4.37 (1H, m), 4.40-4.45 (1H, m),4.49-4.55 (2H, m), 4.99 (2H, m).

Referential Example 33 tert-Butyl2-bromo-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate

Copper(II) bromide (445 mg) was suspended in N,N-dimethylformamide, andtert-butyl nitrite (256 mg) was added dropwise at room temperature.After an N,N-dimethylformamide solution (1 ml) of the compound (400 mg)obtained in Referential Example 32 was added under ice cooling, thereaction mixture was heated and stirred at 60° C. for 1.5 hours. Diethylether and saturated aqueous solution of sodium chloride were added tothe reaction mixture, and the resultant organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:4) to obtain the title compound (174 mg).

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 4.52-4.55 (1H, m), 4.57-4.67 (3H, m).

MS (FAB) m/z: 305 (M+H)⁺.

Referential Example 34 Lithium(5-tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 7 in a similar manner to Referential Example 10.

¹H-NMR (DMSO-d₆) δ: 1.42 (9H, s), 2.69-2.77 (2H, m), 3.60-3.68 (2H, m),4.51-4.58 (2H, m).

Referential Example 35 Methyl2-bromo-4-(2-methoxy-2-oxoethyl)thiazole-5-carboxylate

Copper(II) chloride (26.8 g) was added to a solution of tert-butylnitrite (15.5 g) in acetonitrile (500 ml) at a time under ice cooling. Asolution of methyl 2-amino-5-methoxycarbonylthiazole-4-acetate (YakugakuZasshi, 1966, Vol. 86, p. 300) (23.0 g) in acetonitrile (500 ml) wasadded dropwise to the reaction mixture over 45 minutes, and theresulting mixture was stirred for 1 hour under ice cooling and for 30minutes at room temperature. The solvent was concentrated, and 10%hydrochloric acid and diethyl ether were added to the residue toseparate an organic layer. The organic layer was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:4) to obtain the title compound (25.9 g).

¹H-NMR (CDCl₃) δ: 3.73 (3H, s), 3.87 (3H, s), 4.21 (2H, s).

Referential Example 36 2-[5-(hydroxymethyl)thiazol-4-yl]-1-ethanol

A solution of the compound (23.4 g) obtained in Referential Example 35in tetrahydrofuran (500 ml) was added dropwise over 1 hour to asuspension of lithium aluminum hydride (9.03 g) in tetrahydrofuran (500ml) under ice cooling. After stirring for additional 1 hour under icecooling, water (9 ml), a 35% aqueous solution (9 ml) of sodium hydroxideand water (27 ml) were successively added, and the mixture was stirredat room temperature for 1 hour. After anhydrous magnesium sulfate wasadded to the reaction mixture, and the resultant mixture was stirred,insoluble matter was removed by filtration with Celite, and the filtratewas concentrated. The residue was purified by column chromatography onsilica gel (methanol:methylene chloride=7:93) to obtain the titlecompound (8.64 g).

¹H-NMR (CDCl₃) δ: 3.01 (2H, t, J=5.5 Hz), 3.30 (1H, br.s), 3.57 (1H,br.s), 3.90 (2H, br.s), 4.75 (2H, br.s), 8.66 (1H, s).

MS (ESI) m/z: 160 (M+H)⁺.

Referential Example 372-(5-{[(Methylsulfonyl)oxy]methyl}thiazol-4-yl)ethyl methanesulfonate

A methylene chloride solution of methanesulfonyl chloride (12.6 ml) wasadded dropwise to a solution of the compound (8.64 g) obtained inReferential Example 36 and triethylamine (45.4 ml) dissolved inmethylene chloride (500 ml) over 20 minutes at −78° C. After stirringthe reaction mixture for 15 minutes at −78° C. and 1 hour at 0° C.,water was added to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain the title compound (13.4 g).

¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 3.03 (3H, s), 3.28 (2H, t, J=6.3 Hz),4.61 (2H, t, J=6.3 Hz), 5.44 (2H, s), 8.84 (1H, s).

Referential Example 385-(1-Methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine

1-Methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, Vol. 54, p.1815) (1.89 g) was added to methylene chloride (20 ml) containing thecompound obtained in Referential Example 37 (4.46 g) under ice cooling,and the mixture was stirred overnight at room temperature.1-Methylcyclopropylamine hydrochloride (1.89 g) was additionally added,and the mixture was stirred for 20 hours at room temperature and 5 hoursunder refluxing. Methylene chloride and water were added to the reactionmixture to separate an organic layer. The organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:methylene chloride=1:49) to obtain the titlecompound (944 mg).

¹H-NMR (CDCl₃) δ: 0.40-0.50 (2H, m), 0.68-0.73 (2H, m), 1.16 (3H, s),2.88-2.94 (2H, m), 3.03 (2H, t, J=5.7 Hz), 3.89 (2H, br.s), 8.60 (1H,s).

MS (ESI) m/z: 195 (M+H)⁺.

Referential Example 39 Lithium5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 38 in a similar manner to Referential Example 5.

¹H-NMR (DMSO-d₆) δ: 0.39 (2H, br.s), 0.56 (2H, br.s), 1.10 (3H, br.s),2.66 (2H, br.s), 2.89 (2H, br.s), 3.75 (2H, br.s).

Referential Example 402-[6,7-Dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]-2-methyl-1-propanol

The title compound was obtained from the compound obtained inReferential Example 37 and 2-amino-2-methyl-1-propanol in a similarmanner to Referential Example 38.

¹H-NMR (CDCl₃) δ: 1.15 (6H, s), 2.91 (4H, s), 3.45 (2H, s), 3.87 (2H,s), 8.63 (1H, s).

Referential Example 415-(2-{[tert-Butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

tert-Butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg) wereadded to a solution of the compound obtained in Referential Example 40(1.24 g) in N,N-dimethylformamide (5 ml) at room temperature, and themixture was stirred overnight. Water and diethyl ether were added to thereaction mixture to separate an organic layer. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:2) to obtain thetitle compound (2.46 g).

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.15 (6H, s), 2.83-2.90 (2H, m),2.93-3.00 (2H, m), 3.63 (2H, s), 3.97 (2H, s), 7.35-7.48 (6H, m),7.63-7.70 (4H, m), 8.58 (1H, s).

MS (ESI) m/z: 451 (M+H)⁺.

Referential Example 42 Lithium5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 41 in a similar manner to Referential Example 5.

¹H-NMR (DMSO-d₆) δ: 1.01 (9H, s), 1.11 (6H, s), 2.55-2.65 (2H, m),2.80-2.90 (2H, m), 3.57 (2H, s), 3.80 (2H, br.s), 7.40-7.52 (6H, m),7.60-7.65 (4H, m).

Referential Example 434,7,8,10-Tetrahydro-6H-pyrazolo[1,2-a]thiazolo[4,5-d]pyridazine

1) 4,5-Dimethylthiazole (5.00 g), N-bromosuccinimide (15.7 g) andα,α′-azobisisobutyronitrile (362 mg) were dissolved in ethylenedichloride (500 ml) at room temperature, and the solution was heatedunder reflux for 1 hour. The solvent was distilled off, and the residuewas purified by column chromatography on silica gel (hexane:diethylether=1:4) to obtain 4,5-bis(bromomethyl)thiazole (5.24 g).

¹H-NMR (CDCl₃) δ: 4.64 (2H, s), 4.74 (2H, s), 8.75 (1H, s).

2) 4,5-Bis(bromomethyl)thiazole (1.37 g) and 1,2-trimethylenehydrazinehydrochloride (WO9532965) (732 mg) were suspended in ethanol (15 ml)under ice cooling, and triethylamine (2.82 ml) was added dropwise over 5minutes. After stirring the mixture at room temperature for 2 hours, thesolvent was distilled off, and methylene chloride (50 ml) and asaturated aqueous solution of sodium hydrogencarbonate were added to theresidue to separate an organic layer. The organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:methylene chloride=3:47) to obtain the titlecompound (358 mg).

¹H-NMR (CDCl₃) δ: 2.10-2.25 (2H, m), 3.01 (4H, br.s), 3.95 (2H, s), 3.99(2H, br.s), 8.64 (1H, s).

MS (FAB) m/z: 182 (M+H)⁺.

Referential Example 44 Lithium4,7,8,10-tetrahydro-6H-pyrazolo[1,2-a]thiazolo-[4,5-d]pyridazine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 43 in a similar manner to Referential Example 5.

¹H-NMR (DMSO-d₆) δ: 1.90-2.10 (2H, m), 2.60-3.10 (4H, br.s), 3.65-4.00(4H, m).

Referential Example 454,6,7,8,9,11-Hexahydropyridazino[1,2-a]thiazolo[4,5-d]pyridazine

The title compound was obtained from 4,5-bis(bromomethyl)thiazole (2.20g) obtained in 1) of Referential Example 43 and1,2-tetramethylenehydrazine hydrochloride (U.S. Pat. No. 5,726,126) in asimilar manner to Referential Example 43.

¹H-NMR (CDCl₃) δ: 1.77 (4H, br.s), 2.20-3.50 (4H, br), 3.92 (4H, br.s),8.65 (1H, s).

MS (FAB) m/z: 196 (M+H)⁺.

Referential Example 46 Lithium4,6,7,8,9,11-hexahydropyridazino[1,2-a]thiazolo-[4,5-d]pyridazine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 45 in a similar manner to Referential Example 5.

Referential Example 47 tert-Butyl2-(methylsulfanyl)-5,7-dihydro-6H-pyrrolo-[3,4-d]pyrimidine-6-carboxylate

1-tert-Butoxycarbonyl-3-pyrrolidone (4.57 g) was added toN,N-dimethylformamide dimethyl acetal (30 ml) at room temperature, andthe mixture was heated for 1 hour at 140° C. After allowing the reactionmixture to cool to room temperature, it was concentrated under reducedpressure. Hexane was added to the residue, and yellow powder depositedwas collected by filtration. This powder was dissolved in ethanol (100ml), and methylisothiourea sulfate (9.24 g) and sodium ethoxide (4.52 g)were added to the resultant solution at room temperature, and themixture was heated under reflux for 24 hours. Saturated aqueous solutionof sodium chloride and diethyl ether were added to the reaction mixtureto separate an organic layer. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure, and the residuewas purified by column chromatography on silica gel (methanol:methylenechloride=1:99) to obtain the title compound (1.10 g).

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 2.57 (3H, m), 4.15-4.45 (4H, m), 8.39(½H, s), 8.43 (½H, s).

MS (FAB) m/z: 268 (M+H)⁺.

Referential Example 48 tert-Butyl2-(methylsulfonyl)-5,7-dihydro-6H-pyrrolo-[3,4-d]pyrimidine-6-carboxylate

m-Chloroperbenzoic acid (1.99 g) was added to a methylene chloridesolution (20 ml) of the compound (1.08 g) obtained in ReferentialExample 47 under ice cooling, and the mixture was stirred for 5 hours. Asaturated aqueous solution of sodium sulfite, a saturated aqueoussolution of sodium hydrogen carbonate and methylene chloride were addedto separate an organic layer. The organic layer was then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, hexane was added to the residue, and powder deposited wascollected by filtration to obtain the title compound (1.09 g).

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 3.36 (3H, m), 4.77-4.90 (4H, m), 8.77(½H, s), 8.81 (½H, s).

MS (FAB) m/z: 300 (M+H)⁺.

Referential Example 49 tert-Butyl2-cyano-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

Tetrabutylammonium cyanide (1.04 g) was added to a solution of thecompound (1.05 g) obtained in Referential Example 48 in methylenechloride (30 ml) at room temperature, and the mixture was stirred atroom temperature for 1 hour. 1N sodium hydroxide was added to thereaction mixture to separate an organic layer, and the organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (methylene chloride:acetone=20:1) to obtain the titlecompound (776 mg).

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 4.70-4.85 (4H, m), 8.68-8.77 (1H, m).

MS (FAB) m/z: 247 (M+H)⁺.

Referential Example 50 6-tert-Butyl 2-methyl5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-2,6-dicarboxylate

Concentrated hydrochloric acid (5 ml) was added to a solution of thecompound (776 mg) obtained in Referential Example 49 in methanol (10 ml)at room temperature, and the mixture was stirred at 100° C. for 1 hour.After allowing to cool, the reaction mixture was concentrated underreduced pressure, and the residue was dissolve in methanol (10 ml).Triethylamine (2.20 ml) and di-tert-butyl dicarbonate (1.37 g) wereadded to the solution at room temperature and stirred for 1 hour. Thereaction mixture was concentrated under reduced pressure, and methylenechloride and saturated aqueous solution of sodium chloride were added tothe residue to separate an organic layer, and the organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (methanol:methylene chloride=3:97) to obtain the titlecompound (317 mg).

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 4.09 (3H, s), 4.75-4.85 (4H, m), 8.81(½H, s), 8.85 (½H, s).

MS (FAB) m/z: 280 (M+H)⁺.

Referential Example 51 Lithium5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine-2-carboxylate

1) After 4,5-bis(bromomethyl)thiazole (600 mg) obtained in 1) ofReferential Example 43 was dissolved in ethanol (20 ml), and1,2-dimethylhydrazine hydrochloride (294 mg) was added under icecooling, triethylamine (1.23 ml) was added at a time, and the mixturewas stirred for 30 minutes at room temperature and 30 minutes at 50° C.The solvent was distilled off, and the residue was purified by columnchromatography on silica gel (methanol:methylene chloride=1:19) toobtain 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine (90 mg).

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 2.56 (3H, s), 3.92 (2H, s), 4.06 (2H,br.s), 8.68 (1H, s).

MS (FAB) m/z: 170 (M+H)⁺.

2) The title compound was obtained from5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine in a similarmanner to Referential Example 5.

¹H-NMR (DMSO-d₆) δ: 2.28 (3H, s), 2.39 (3H, s), 3.66 (2H, br.s), 3.88(2H, br.s).

Referential Example 52 4-Nitrophenyl 5-chloroindole-2-carboxylate

After 5-chloroindole-2-carboxylic acid (20 g) was suspended in methylenechloride (1500 ml), and N,N-dimethylformamide (2 ml) was added, thionylchloride (11 ml) was added dropwise at room temperature. The reactionmixture was heated overnight under reflux and then concentrated underreduced pressure. The residue was dissolved in methylene chloride (1000ml), and triethylamine (84.7 ml) and p-nitrophenol (14.2 g) were addedto the mixture under ice cooling. After stirring for 1 hour at roomtemperature, the reaction mixture was concentrated under reducedpressure, and ethyl acetate and 0.2N hydrochloric acid were added to theresidue to separate an organic layer. The organic layer was successivelywashed with a saturated aqueous solution of sodium hydrogencarbonate andsaturated aqueous solution of sodium chloride and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain the title compound (29.9 g).

¹H-NMR (CDCl₃) δ: 7.35 (1H, dd, J=9.0, 1.7 Hz), 7.39-7.42 (2H, m), 7.45(2H, dd, J=7.3, 1.7 Hz), 7.73 (1H, d, J=1.0 Hz), 8.35 (2H, dd, J=7.3,1.7 Hz), 9.09 (1H, br.s).

MS (FD) m/z: 316 (M⁺).

Referential Example 53 6-Chloro-2-quinolinecarbonitrile

6-Chloroquinoline (2.50 g) was dissolved in methylene chloride (25 ml),and m-chloroperbenzoic acid (3.71 g) was added under ice cooling to stirthe mixture at room temperature for 1 hour. After the reaction mixturewas diluted with methylene chloride, the diluted mixture was washed withan aqueous solution of sodium thiosulfate and an aqueous solution ofsodium hydroxide and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was dissolvedin methylene chloride (40 ml), and trimethylsilyl cyanide (2.0 ml) andN,N-dimethylcarbamoyl chloride (1.50 ml) were added to heat theresultant mixture for 9 hours under reflux. After trimethylsilyl cyanide(1.0 ml) and N,N-dimethylcarbamoyl chloride (0.80 ml) were additionallyadded, and the mixture was heated for 16 hours under reflux, thereaction mixture was diluted with methylene chloride, and a 10% aqueoussolution (40 ml) of potassium carbonate was added to stir the mixturefor 30 minutes. After an organic layer was separated and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure. Methylene chloride was added to the residue, and crystalsdeposited were collected by filtration to obtain the title compound(1.77 g). Further, a mother liquor was purified by column chromatographyon silica gel (methylene chloride) to obtain the title compound (0.80g).

¹H-NMR (DMSO-d₆) δ: 7.94 (1H, dd, J=9.0, 2.2 Hz), 8.09 (1H, d, J=8.5Hz), 8.15 (1H, d, J=9.0 Hz), 8.29 (1H, d, J=2.2 Hz), 8.63 (1H, d, J=8.5Hz).

MS (FAB) m/z: 189 (M+H)⁺.

Referential Example 54 6-Chloro-2-quinolinecarboxylic acid

The compound (1.73 g) obtained in Referential Example 53 was dissolvedin concentrated hydrochloric acid (40 ml), and the solution was heatedfor 19 hours under reflux. The reaction mixture was cooled to roomtemperature, and deposits were collected by filtration and then washedwith water to obtain the title compound (1.81 g).

¹H-NMR (DMSO-d₆) δ: 7.87 (1H, dd, J=9.0, 2.4 Hz), 8.10-8.20 (2H, m),8.24 (1H, d, J=2.2 Hz), 8.52 (1H, d, J=8.5 Hz).

MS (FAB) m/z: 208 (M+H)⁺.

Referential Example 55 Methyl3-(4-chlorophenyl)-2-(formylamino)propionate

(±)-(4-Chlorophenyl)alanine methyl ester hydrochloride (2.00 g) wassuspended in methylene chloride (20 ml), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.60 g),1-hydroxybenzotriazole monohydrate (1.23 g), N-methylmorpholine (1.90ml) and formic acid (0.30 ml) were added to stir the mixture for 15minutes. After a process in which formic acid (0.30 ml) was additionallyadded to stir the mixture for 15 minutes was repeated 3 times, thereaction mixture was diluted with methylene chloride. After an organiclayer was washed with water and then dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=40:1) to obtain the title compound (1.21 g).

¹H-NMR (CDCl₃) δ: 3.10 (1H, dd, J=13.9, 5.6 Hz), 3.18 (1H, dd, J=13.9,5.9 Hz), 3.75 (3H, s), 4.95 (1H, m), 6.07 (1H, br), 7.05 (2H, d, J=8.3Hz), 7.27 (2H, d, J=8.3 Hz), 8.18 (1H, s).

MS (FAB) m/z: 242 (M+H)⁺.

Referential Example 56 Methyl 7-chloro-3-isoquinolinecarboxylate

The compound (1.45 g) obtained in Referential Example 55 was dissolvedin methylene chloride (40 ml), and oxalyl chloride (0.57 ml) was addeddropwise. After the mixture was stirred at room temperature for 30minutes, ferric chloride (1.17 g) was added at an ambient temperature ofabout −10° C. to stir the mixture at room temperature for 4 days. 1NHydrochloric acid was added, and the resultant mixture was diluted withmethylene chloride to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was dissolved in methanol (38 ml), andconcentrated sulfuric acid (2 ml) was added to heat the mixture for 20hours under reflux. An aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture, the resultant mixture was extracted withmethylene chloride, and the extract was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1→ethyl acetate) to obtain the title compound(0.25 g).

¹H-NMR (CDCl₃) δ: 4.07 (3H, s), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.94 (1H,d, J=8.8 Hz), 8.06 (1H, d, J=2.0 Hz), 8.59 (1H, s), 9.28 (1H, s).

Referential Example 57 7-Chloro-3-chloroisoquinolinecarboxylichydrochloride

The compound (0.23 g) obtained in Referential Example 56 was dissolvedin concentrated hydrochloric acid (10 ml) to heat the mixture for 18hours under reflux. The temperature of the reaction mixture was droppedto room temperature, and deposits were collected by filtration and thenwashed with water to obtain the title compound (0.21 g).

¹H-NMR (DMSO-d₆) δ: 7.96 (1H, m), 8.29 (1H, d, J=8.5 Hz), 8.44 (1H, s),8.72 (1H, s), 9.45 (1H, d, J=6.6 Hz).

MS (FAB) m/z: 208 (M+H)⁺.

Referential Example 58(3R)-1-Benzyl-3-(tert-butyldiphenylsilyloxy)pyrrolidine

(3R)-1-Benzyl-3-hydroxypyrrolidine (500 μl) and imidazole (466 mg) weredissolved in N,N-dimethylformamide (15 ml), tert-butyldiphenylsilylchloride (1.57 ml) was added under ice cooling, and the mixture wasstirred at room temperature for 9 days. After the solvent was distilledoff under reduced pressure, and methylene chloride and water were addedto the residue to conduct liquid separation, the resultant organic layerwas dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was subjected to flash columnchromatography on silica gel (hexane:ethyl acetate=3:1) to obtain thetitle compound (1.27 g).

¹H-NMR (CDCl₃) δ: 1.05 (9H, s), 1.70-1.85 (1H, m), 1.90-2.00 (1H, m),2.45-2.65 (3H, m), 2.70-2.80 (1H, m), 3.50-3.70 (2H, m), 4.35-4.45 (1H,m), 7.20-7.45 (11H, m), 7.60-7.70 (4H, m).

MS (ESI) m/z: 416 (M+H)⁺.

Referential Example 59N-[(1R*,2S*)-2-Aminocyclopropyl]-5-chloroindole-2-carboxamide

1-Hydroxybenzotriazole monohydrate (377 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (642 mg) anddiisopropylethylamine (1.95 ml) were added to a solution ofcis-1,2-cyclopropanediamine hydrochloride (J. Med. Chem., 1998, Vol. 41,pp. 4723-4732) (405 mg) and 5-chloroindole-2-carboxylic acid (546 mg) inN,N-dimethylformamide (10 ml) at room temperature, and the mixture wasstirred for 50 hours. After the reaction mixture was concentrated underreduced pressure, methylene chloride (50 ml) and a saturated solution(200 ml) of sodium hydrogencarbonate were added to separate colorlesssolid deposited by filtration. The filtrate was extracted with methylenechloride. After the resultant organic layers were combined and driedover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure to obtain residue. The residue was purified by flashcolumn chromatography on silica gel (methylenechloride:methanol=100:7→10:1) to obtain the title compound (110 mg).

¹H-NMR (DMSO-d₆) δ: 0.44 (1H, dd, J=10.7, 4.4 Hz), 1.11 (1H, dd, J=14.0,7.4 Hz), 2.63-2.70 (1H, m), 3.07-3.16 (1H, m), 6.77 (1H, s), 6.97 (1H,br.s), 7.23 (1H, dd, J=8.9, 1.8 Hz), 7.36 (1H, d, J=8.9 Hz), 7.60 (1H,s), 9.32 (1H, s).

MS (FAB) m/z: 250 (M+H)⁺.

Referential Example 60N-[(1R*,2S*)-2-Aminocyclobutyl]-5-chloroindole-2-carboxamide

The title compound was obtained from cis-1,2-cyclobutanediaminehydrochloride (J. Am. Chem. Soc., 1942, Vol. 64, pp. 2696-2700) in asimilar manner to Referential Example 59.

¹H-NMR (DMSO-d₆) δ: 1.55-2.20 (4H, m), 3.52-3.62 (1H, m), 4.35-4.50 (1H,m), 7.16 (1H, dd, J=8.7, 2.1 Hz), 7.19 (1H, s), 7.42 (1H, d, J=8.7 Hz),7.70 (1H, d, J=2.1 Hz), 8.36 (1H, d, J=7.8 Hz), 11.77 (1H, br.s).

MS (ESI) m/z: 264 (M+H)⁺.

Referential Example 61 tert-Butyl (1R*,2R*)-2-aminocyclopentylcarbamate

(±)-trans-1,2-Cyclopentanediamine (WO98/30574) (692 mg) was dissolved inmethylene chloride (10 ml), to which triethylamine (1.1 ml) and2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) wereadded, and the mixture was stirred at 0° C. for 1 hour. Thereafter,2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) wereadditionally added, and the mixture was stirred at room temperature for7 hours. Water was added to the reaction mixture to separate an organiclayer. The organic layer was washed with saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. The residue waspurified by flash column chromatography on silica gel (methylenechloride:methanol=9:1) to obtain the title compound (395 mg).

¹H-NMR (CDCl₃) δ: 1.25-1.40 (2H, m), 1.49 (9H, s), 1.59-1.77 (2H, m),1.92-2.08 (1H, m), 2.10-2.17 (1H, m), 2.98 (1H, q, J=7.2 Hz), 3.48-3.53(1H, m), 4.49 (1H, br.s).

MS (ESI) m/z: 201 (M+H)⁺.

Referential Example 62N-[(1R*,2R*)-2-Aminocyclopentyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (175 mg) obtained in Referential Example 61 was dissolvedin N,N-dimethylformamide (3 ml), and to the solution lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(purity: 90%, 258 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (252 mg) and 1-hydroxybenzotriazole monohydrate (60 mg)were added. The mixture was stirred at room temperature for 2 days. Thesolvent was distilled off under reduced pressure using a pump, andmethylene chloride and a saturated solution of sodium hydrogencarbonatewere added to the residue to separate an organic layer. The resultantorganic layer was washed with saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (methylene chloride:methanol=47:3).The resultant pale yellow oil was dissolved in a ethanol solution (5 ml)of hydrochloric acid, and the solution was stirred at room temperaturefor 1 hour. Ethyl acetate was then added, and the solvent was distilledoff under reduced pressure. Ethyl acetate was added to the residue tocollect precipitate formed by filtration, thereby obtaining the titlecompound (120 mg).

¹H-NMR (DMSO-d₆) δ: 1.63-1.73 (4H, m), 1.99-2.06 (2H, m), 2.91 (3H, s),3.09-3.14 (1H, m), 3.25-3.70 (4H, m), 4.27-4.32 (1H, m), 4.42-4.46 (1H,m), 4.68-4.71 (1H, m), 8.20-8.23 (3H, m), 9.09 (1H, d, J=8.3 Hz),11.82-12.01 (1H, m).

MS (ESI) m/z: 281 (M+H)⁺.

Referential Example 63N-[(1R*,2R*)-2-Aminocyclopentyl]-5-chloro-1H-indol-2-carboxamidehydrochloride

The compound (1.40 g) obtained in Referential Example 61 was dissolvedin N,N-dimethylformamide (15 ml), and to the solution5-chloroindole-2-carboxylic acid (1.64 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g) and1-hydroxybenzotriazole monohydrate (473 mg) were added. The mixture wasstirred at room temperature for 23 hours. The solvent was distilled offunder reduced pressure, and methylene chloride and a saturated solutionof sodium hydrogencarbonate were added to the residue to collectprecipitates by filtration. The precipitates were washed with ethylacetate, methylene chloride and methanol. On the other hand, thefiltrate was separated to give an organic layer, which was taken out anddried over anhydrous sodium sulfate, and the solvent was then distilledoff under reduced pressure. The residue was purified by flash columnchromatography on silica gel (methylene chloride:methanol=19:1) toobtain a pale yellow solid. This pale yellow solid was combined with theprecipitates obtained by the filtration and dissolved in methylenechloride (10 ml), and trifluoroacetic acid (10 ml) was added to stir themixture at room temperature for 3 hours. The solvent was distilled offunder reduced pressure, and methylen chloride and 1N aqueous solution ofsodium hydroxide were added to the residue to collect precipitate byfiltration. The organic layer of the filtrate was separated and driedover anhydrous sodium sulfate. The precipitates collected by thefiltration were added to this solution, and a 4N dioxane solution (20ml) of hydrochloric acid was further added. The solvent was distilledoff under reduced pressure, and methylene chloride (10 ml) and a 4Ndioxane solution (10 ml) of hydrochloric acid were added to the residue.The solvent was distilled off again under reduced pressure. Ethylacetate was added to the residue to collect precipitates formed byfiltration, thereby obtaining the title compound (1.83 g).

¹HNMR (DMSO-d₆) δ: 1.60-1.75 (4H, m), 2.05-2.10 (2H, m), 3.49 (1H, q,J=7.6 Hz), 4.27 (4H, quintet, J=7.6 Hz), 7.17 (1H, d, J=8.6 Hz), 7.19(1H, s), 7.42 (1H, d, J=8.6 Hz), 7.70 (1H, s), 8.24 (3H, br.s), 8.85(1H, d, J=7.3 Hz), 11.91 (1H, s).

MS (ESI) m/z: 278 (M+H)⁺.

Referential Example 64 tert-Butyl (1R*,2R*)-2-aminocyclohexylcarbamate

The title compound was obtained from (±)-trans-1,2-cyclohexanediamine ina similar manner to Referential Example 61.

m.p. 79-81.

¹H-NMR (CDCl₃) δ: 1.05-1.34 (4H, m), 1.45 (9H, s), 1.68-1.75 (2H, m),1.92-2.02 (2H, m), 2.32 (1H, dt, J=10.3, 3.9 Hz), 3.08-3.20 (1H, m),4.50 (1H, br.s).

MS (FAB) m/z: 215 (M+H)⁺.

Referential Example 65N-[(1R*,2R*)-2-Aminocyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidetrifluoroacetate (hydrochloride)

The title compound was obtained from the compound obtained inReferential Example 64 in a similar manner to Referential Example 62.

¹H-NMR (DMSO-d₆) δ: 1.10-1.80 (7H, m), 1.95-2.05 (1H, m), 2.97 (3H, s),3.00-3.20 (3H, m), 3.63 (2H, br.s), 3.72-3.88 (1H, m), 4.61 (2H, br.s),7.98 (3H, s), 8.89 (1H, d, J=9.2 Hz).

MS (FAB) m/z: 295 (M+H)⁺.

The hydrochloride was obtained in a similar manner.

Referential Example 66 tert-Butyl (1R*,2S*)-2-aminocyclohexylcarbamate

The title compound was obtained from cis-1,2-cyclohexanediamine in asimilar manner to Referential Example 61.

¹H-NMR (CDCl₃) δ: 1.30-1.70 (17H, m), 2.98-3.05 (1H, m), 3.60 (1H,br.s), 4.98 (1H, br.s).

MS (FAB) m/z: 215 (M+H)⁺.

Referential Example 67N-[(1R*,2S*)-2-Aminocyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride (trifluoroacetate)

The title compound was obtained from the compound obtained inReferential Example 66 in a similar manner to Referential Example 62.

¹H-NMR (DMSO-d₆) δ: 1.30-1.90 (8H, m), 2.92 (3H, s), 3.05-3.79 (5H, m),4.23 (1H, br.s), 4.34-4.79 (2H, m), 8.01-8.34 (3H, m), 8.30-8.49 (1H,m), 11.90-12.30 (1H, m).

MS (FAB) m/z: 295 (M+H)⁺.

The trifluoroacetate was obtained in a similar manner.

Referential Example 68 tert-Buthyl(1R*,2R*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate

5-Chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzotriazolemonohydrate (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.95 g) were added to a solution of the compound (3.00 g)obtained in Referential Example 64 in N,N-dimethylformamide (10 ml) atroom temperature. After stirring for 3 days, the reaction mixture wasconcentrated under reduced pressure, and methylene chloride (30 ml), asaturated aqueous solution of sodium hydrogencarbonate (150 ml) andwater (150 ml) were added to the residue. After collecting colorlessprecipitate formed by filtration and the precipitate was dried to obtainthe title compound (5.21 g).

¹H-NMR (DMSO-d₆) δ: 1.10-1.45 (4H, m), 1.21 (9H, s), 1.68 (2H, d, J=8.1Hz), 1.86 (2H, t, J=16.2 Hz), 3.22-3.42 (1H, m), 3.69 (1H, br.s), 6.66(1H, d, J=8.5 Hz), 7.02 (1H, s), 7.15 (1H, dd, J=8.5, 2.0 Hz), 7.41 (1H,d, J=8.5 Hz), 7.67 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=8.1 Hz), 11.73 (1H,br.s).

MS (ESI) m/z: 392 (M+H)⁺.

Referential Example 69N-[(1R*,2R*)-2-Aminocyclohexyl]-5-chloroindole-2-carboxamidehydrochloride

An ethanol solution (100 ml) of hydrochloric acid was added to asolution of the compound (5.18 g) obtained in Referential Example 68 inmethylene chloride (100 ml) at room temperature. After stirring for 2days, the reaction mixture was concentrated under reduced pressure,diethyl ether (300 ml) was added to the resultant residue, and colorlessprecipitate formed was collected by filtration and dried to obtain thetitle compound (4.30 g).

¹H-NMR (DMSO-d₆) δ: 1.20-1.36 (2H, m), 1.36-1.50 (2H, m), 1.60 (2H,br.s), 1.90 (1H, d, J=13.0 Hz), 2.07 (1H, d, J=13.7 Hz), 3.06 (1H,br.s), 3.83-3.96 (1H, m), 7.15-7.24 (2H, m), 7.45 (1H, d, J=8.6 Hz),7.73 (1H, s), 8.00 (3H, br.s), 8.60 (1H, d, J=8.3 Hz), 11.86 (1H, s).

MS (ESI) m/z: 292 (M+H)⁺.

Referential Example 70 tert-Buthyl(1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 66 in a similar manner to Referential Example 68.

¹H-NMR (DMSO-d₆) δ: 1.20-1.45 (11H, m), 1.45-1.70 (4H, m), 1.70-1.85(2H, m), 3.76 (1H, br.s), 4.08 (1H, br.s), 6.64 (1H, d, J=7.6 Hz), 7.12(1H, s), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.43 (1H, d, J=8.8 Hz), 7.69 (1H,d, J=2.0 Hz), 7.85 (1H, d, J=6.9 Hz), 11.80 (1H, br.s).

MS (ESI) m/z: 392 (M+H)⁺.

Referential Example 71N-[(1R*,2S*)-2-Aminocyclohexyl]-5-chloroindole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 70 in a similar manner to Referential Example 69.

¹H-NMR (DMSO-d₆) δ: 1.30-1.50 (2H, m), 1.55-1.95 (6H, m), 3.41 (1H,br.s), 4.32 (1H, br.s), 7.19 (1H, dd, J=8.7, 2.0 Hz), 7.33 (1H, s), 7.45(1H, d, J=8.7 Hz), 7.60-7.90 (4H, m), 8.17 (1H, d, J=7.1 Hz), 11.91 (1H,s).

MS (FAB) m/z: 292 (M+H)⁺.

Referential Example 72 (1R*,2R*)-1,2-Cycloheptanediol

Cycloheptene (3.85 g) was added portionwise to 30% aqueous hydrogenperoxide (45 ml) and 88% formic acid (180 ml), and the mixture wasstirred at 40 to 50° C. for 1 hour and then at room temperature for anight. The solvent was distilled off under reduced pressure, and a 35%aqueous solution of sodium hydroxide was added to the residue toalkalify it. After this residue was stirred at 40 to 50° C. for 10minutes, ethyl acetate was added to conduct liquid separation. Theresultant water layer was extracted 4 times with ethyl acetate. Theresultant organic layers were collected and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure toobtain the title compound (4.56 g).

¹H-NMR (CDCl₃) δ: 1.44-1.56 (6H, m), 1.63-1.70 (2H, m), 1.83-1.91 (2H,m), 2.91 (2H, br.s), 3.40-3.44 (2H, m).

MS (FAB) m/z: 131 (M+H)⁺.

Referential Example 73 (1R*,2R*)-1,2-Cycloheptanediamine hydrochloride

The compound (4.56 g) obtained in Referential Example 72 was dissolvedin methylene chloride (35 ml), triethylamine (29 ml) was added, and themixture was cooled to −78° C. Methanesulfonyl chloride (8.13 ml) wasadded dropwise thereto. Methylene chloride (10 ml) was slowly added, andthe mixture was stirred for 20 minutes at the same temperature and thenfor 1.5 hours at 0° C. Water was added to the reaction mixture toconduct liquid separation, and the resultant organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate and driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain an oil. This oil was dissolved inN,N-dimethylformamide (90 ml), sodium azide (13.65 g) was added, and themixture was stirred at 65° C. for 18 hours. Ether and water was added tothe reaction mixture to conduct liquid separation. The resultant etherlayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain an oil.

This oil was dissolved in ethanol (70 ml), 10% palladium on carbon(containing 50% of water, 4 g) was added, and the mixture was stirredfor 4 days in a hydrogen (3.5 atm) atmosphere. After separating thepalladium on carbon by filtration, a 1N ethanol solution (70 ml) ofhydrochloric acid was added to the filtrate, and the solvent wasdistilled off under reduced pressure. The residue was dissolved inmethanol, ethyl acetate was added, and the solvent was distilled offunder reduced pressure again. Precipitate formed was collected byfiltration to obtain the title compound (3.57 g).

¹H-NMR (DMSO) δ: 1.44 (4H, br.s), 1.73-1.81 (6H, m), 3.43 (2H, br.s),8.63 (6H, br.s).

MS (ESI) m/z: 129 (M+H)⁺.

Referential Example 74N-[(1R*,2R*)-2-Aminocycloheptyl]-5-chloroindole-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 73 in a similar manner to Referential Example 59.

¹H-NMR (DMSO-d₆) δ: 1.49-1.52 (4H, m), 1.72-1.91 (6H, m), 4.04-4.10 (1H,m), 7.17-7.23 (2H, m), 7.44 (1H, d, J=8.8 Hz), 7.72 (1H, d, J=2.0 Hz),7.96 (2H, br.s), 8.75 (1H, d, J=8.5 Hz), 11.89 (1H, br.s).

MS (ESI) m/z: 306 (M+H)⁺.

Referential Example 75 (1R*,2S*)-1,2-Cyclooctanediol

Cyclooctene (4.41 g) was dissolved in acetonitrile (45 ml) and water (15ml), and to the solution N-methylmorpholine N-oxide (5.15 g) andmicrocapsulated osmium tetroxide (1 g, containing 10% osmium tetroxide)were added, and the mixture was stirred at 40 to 50° C. for 21 hours.Insoluble microcapsulated osmium tetroxide was removed by filtration,and washed with acetonitrile, and the filtrate was concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (hexane:ethyl acetate=1:1) to obtain thetitle compound (4.97 g).

¹H-NMR (CDCl₃) δ: 1.48-1.58 (6H, m), 1.64-1.75 (4H, m), 1.86-1.96 (2H,m), 2.28 (2H, d, J=2.9 Hz), 3.90 (2H, d, J=8.3 Hz).

MS (FAB) m/z: 145 (M+H)⁺.

Referential Example 76 (1R*,2S*)-1,2-diazidocyclooctane

After cis-1,2-cyclooctanediol (4.82 g) was dissolved in methylenechloride (60 ml), and to the solution triethylamine (27.7 ml) was added,and the interior of a vessel was purged with argon, the mixture wascooled to −78° C., and methanesulfonyl chloride (7.7 ml, 100 mmol) wasadded dropwise thereto. The mixture was stirred for 1 hour at the sametemperature and then for 1 hour at 0° C. Water was then added to thereaction mixture to conduct liquid separation, and the resultant organiclayer was washed with water, 0.5N hydrochloric acid, water and asaturated aqueous solution of sodium hydrogencarbonate and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was dissolved in N,N-dimethylformamide (80ml), sodium azide (13.0 g) was added, and the mixture was stirred at 65°C. for 19 hours. Ether and water was added to the reaction mixture toconduct liquid separation. The resultant ether layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by flash column chromatography on silica gel(hexane:ethyl acetate=6:1) to obtain the title compound (4.85 g).

¹H-NMR (CDCl₃) δ: 1.49-1.64 (6H, m), 1.67-1.78 (2H, m), 1.81-1.97 (4H,m), 3.74-3.76 (2H, m).

Referential Example 77 (1R*,2S*)-1,2-Cyclooctanediamine hydrochloride

The compound (4.85 g) obtained in Referential Example 76 was dissolvedin ethanol (55 ml), to the solution 10% palladium on carbon (containing50% of water, 3.0 g) was added, and the mixture was stirred for 21 hoursin a hydrogen (4.5 atm) atmosphere. After separating the catalyst byfiltration, a 1N ethanol solution (50 ml) of hydrochloric acid was addedto the filtrate, and the solvent was distilled off under reducedpressure. Ethyl acetate was added to the residue, and precipitate formedwas collected by filtration to obtain the title compound (4.14 g).

¹H-NMR (DMSO) δ: 1.51 (6H, br.s), 1.69 (2H, br.s), 1.79-1.99 (4H, m),3.68-3.70 (2H, m), 8.66 (6H, br.s).

MS (ESI) m/z: 143 (M+H)⁺.

Referential Example 78N-[(1R*,2S*)-2-aminocyclooctyl]-5-chloroindole-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 77 in a similar manner to Referential Example 59.

MS (ESI) m/z: 320 (M+H)⁺.

Referential Example 79 (1R*,2R*)-4-Methoxy-1,2-cyclopentanediol (mixtureof 4-position stereoisomers)

60% Sodium hydride (800 mg) was added portionwise to a solution of3-cyclopentene-1-ol (1.68 g) and methyl iodide (1.25 ml) dissolved intetrahydrofuran (20 ml) under ice cooling, and the mixture was stirredovernight at room temperature. Water and diethyl ether was added to thereaction mixture to separate an organic layer, the organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure with ice cooling to obtain crude4-methoxy-1-cyclopentene.

88% Formic acid (90 ml) and 30% hydrogen peroxide (3.17 ml) were addedto 4-methoxy-1-cyclopentene thus obtained, and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and a 35% aqueous solution of sodium hydroxidewas added to the residue to alkalify the reaction mixture, followed bystirring at 50° C. for 10 minutes. The reaction mixture was cooled toroom temperature and extracted with ethyl acetate to dry the organiclayer over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified by column chromatography on silica gel(methanol:methylene chloride=1:19) to obtain the title compound (1.21g).

¹H-NMR (CDCl₃) δ: 1.65-1.85 (2H, m), 2.15-2.30 (2H, m), 3.28 (3H, s),3.90-4.00 (2H, m), 4.26 (1H, br.s).

Referential Example 80 (1R*,2R*)-1,2-Diazido-4-methoxycyclopentane(mixture of 4-position stereoisomers)

The compound (1.21 g) obtained in Referential Example 79 andtriethylamine (7.66 ml) were dissolved in methylene chloride (20 ml),and methanesulfonyl chloride (2.13 ml) was added dropwise over 20minutes at −78° C. After completion of drop addition, the mixture waswarmed to 0° C. and stirred for 80 minutes to obtain crude(1R*,2R*)-1,2-bis(methanesulfonyloxy)-4-methoxycyclopentane. Thisproduct was dissolved in N,N-dimethylformamide (20 ml), and sodium azide(3.57 g) was added to heat and stir the mixture at 65° C. for 22 hours.Sodium azide (3.57 g) was additionally added to stir the mixture at 70°C. for 2 days. The reaction mixture was allowed to cool, and water anddiethyl ether was added to separate an organic layer. The organic layerwas dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the residue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1) to obtain the title compound (584 mg).

¹H-NMR (CDCl₃) δ: 1.65-1.80 (2H, m), 2.05-2.18 (1H, m), 2.25-2.40 (1H,m), 3.21 (3H, s), 3.55-3.65 (1H, m), 3.75-3.90 (2H, m).

Referential Example 81 (1R*,2R*)-4-Methoxy-1,2-cyclopentane diaminehydrochloride (mixture of 4-position stereoisomers)

The compound (584 mg) obtained in Referential Example 80 was dissolvedin ethanol, and 10% palladium on carbon (321 mg) was added to conducthydrogenation at normal temperature and normal pressure for 2 days.After removing the catalyst by filtration, the reaction mixture wasconcentrated, and a 1N ethanol solution of hydrochloric acid and ethylacetate were added to the residue. The mixture was concentrated toobtain the title compound (488 mg).

¹H-NMR (CDCl₃) δ: 1.72-1.83 (1H, m), 1.91-2.03 (1H, m), 2.07-2.18 (1H,m), 2.37-2.50 (1H, m), 3.19 (3H, s), 3.55-3.75 (2H, br), 3.85-3.95 (1H,m), 8.60-8.90 (6H, br).

MS (ESI) m/z: 261 (2M+H)⁺.

Referential Example 82N-[(1R*,2R*)-2-Amino-4-methoxycyclopentyl]-5-chloroindole-2-carboxamide(mixture of 4-position stereoisomers)

The compound (470 mg) obtained in Referential Example 81 was suspendedin N,N-dimethylformamide (5 ml), and triethylamine (0.966 ml) andp-nitrophenyl 5-chloroindole-2-carboxylate (805 mg) was added. Themixture was stirred at room temperature for 4 days. After the solventwas distilled off under reduced pressure, and methylene chloride and asaturated aqueous solution of sodium hydrogencarbonate were added toconduct liquid separation, an organic layer was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methanol:methylene chloride=1:9) to obtain the title compound (268 mg).

Referential Example 83(1R*,2R*)-4-[(Benzyloxy)methyl]-1,2-cyclopentanediol (mixture of4-position stereoisomers)

The title compound was obtained by benzylating4-hydroxymethyl-1-cyclopentene (J. Heterocycl. Chem., 1989, Vol. 26, p.451) with benzyl bromide and then reacting the product with formicacid-hydrogen peroxide in a similar manner to Referential Example 79.

¹H-NMR (CDCl₃) δ: 1.44-1.52 (1H, m), 1.77-1.85 (1H, m), 1.89-1.97 (1H,m), 2.25-2.35 (1H, m), 2.46-2.58 (1H, m), 3.40-3.50 (2H, m), 3.89 (1H,br.s), 4.08 (1H, br.s), 4.54 (2H, s), 7.27-7.39 (5H, m).

MS (FAB) m/z: 223 (M+H)⁺.

Referential Example 84(1R*,2R*)-4-[(Benzyloxy)methyl]-1,2-cyclopentanediamine (mixture of4-position stereoisomers)

(1R*,2R*)-4-Benzyloxymethyl-1,2-diazidocyclopentane was obtained fromthe compound obtained in Referential Example 83 in a similar manner toReferential Example 80. The title compound was obtained in a similarmanner to Referential Example 81 without purifying this product.

Referential Example 85N-{(1R*,2R*)-2-Amino-4-[(benzyloxy)methyl]cyclopentyl}-5-chloroindole-2-carboxamide(mixture of 4-position stereoisomers)

The title compound was obtained from the compound obtained inReferential Example 84 in a similar manner to Referential Example 59.

¹H-NMR (DMSO-d₆) δ: 1.07-1.15 (0.5H, m), 1.26-1.35 (0.5H, m), 1.47-1.55(0.5H, m), 1.61-1.79 (1H, m), 1.83-1.92 (0.5H, m), 1.99-2.10 (0.5H, m),2.12-2.20 (0.5H, m), 2.27-2.40 (1H, m), 3.10-3.20 (1H, m), 3.33-3.39(2H, m), 3.81-3.92 (1H, m), 4.48 (2H, s), 7.13-7.20 (2H, m), 7.22-7.39(5H, m), 7.43 (1H, d, J=8.5 Hz), 7.69 (1H, d, J=2.2 Hz), 8.34 (1H, t,J=7.1 Hz).

MS (FAB) m/z: 398 (M+H)⁺.

Referential Example 86 Ethyl(1R*,3R*,6S*)-7-oxabicyclo[4.1.0]heptane-3-carbooxylate

(1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org. Chem.,1996, Vol. 61, p. 8687) (14.3 g) was dissolved in ethanol (130 ml), a 2Naqueous solution (34.5 ml) of sodium hydroxide was added under icecooling, and the mixture was then stirred at room temperature for 7hours. After the solvent was distilled off under reduced pressure, andwater was added to the residue to conduct extraction with methylenechloride, the extract was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (hexane:ethylacetate=83:17) to obtain the title compound (6.54 g).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 1.50-1.70 (2H, m), 1.71-1.82(1H, m), 2.08-2.28 (4H, m), 3.16 (2H, s), 4.12 (2H, q, J=7.1 Hz).

Referential Example 87 Ethyl(1R*,3S*,4S*)-3-azido-4-hydroxycyclohexanecarboxylate

The compound (13.6 g) obtained in Referential Example 86 was dissolvedin N,N-dimethylformamide (100 ml), ammonium chloride (6.45 g) and sodiumazide (7.8 g) were successively added at room temperature, and themixture was then stirred at 75° C. for 12 hours. The solvent wasconcentrated to about 1/3, and the residue was diluted with water andethyl acetate to conduct stirring for 3 minutes. The resultant organiclayer was washed with water and saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane=1:4) to obtainthe title compound (15.8 g).

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 1.37-1.67 (2H, m), 1.86-1.95(1H, m), 2.04-2.18 (2H, m), 2.32-2.43 (1H, m), 2.68-2.78 (1H, m),3.40-3.60 (2H, m), 4.17 (2H, q, J=7.1 Hz).

Referential Example 88 Ethyl(1R*,3S*,4S*)-3-[(tert-butoxycarbonyl)amino]]-4-hydroxycyclohexanecarboxylate

The compound (100 mg) obtained in Referential Example 87 anddi-tert-butyl dicarbonate (133 mg) were dissolved in ethyl acetate (12ml) and a catalytic amount of 10% palladium on carbon was added to stirthe mixture at room temperature for 12 hours in a hydrogen atmosphere.After insoluble matter was removed by filtration, the solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=3:1) to obtainthe title compound (145 mg).

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 1.45 (9H, s), 1.38-1.57 (2H,m), 1.86-1.95 (1H, m), 2.05-2.17 (1H, m), 2.29-2.39 (2H, m), 2.61-2.68(1H, m), 3.25-3.66 (3H, m), 4.17 (2H, q, J=7.1 Hz), 4.53 (1H, br.s).

Referential Example 89 Ethyl(1R*,3S*,4R*)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylateand ethyl(1R*,3S*,4S*)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

After the compound (16 g) obtained in Referential Example 88 andtriethylamine (38 ml) were dissolved in methylene chloride (150 ml), andthe solution was cooled to −78° C., methanesulfonyl chloride (13 ml) wasadded dropwise at the same temperature. After stirring for 15 minutes atthe same temperature, the mixture was heated to 0° C. and stirred for 30minutes and then 2 hours at room temperature. After 0.1N hydrochloricacid was added, and the mixture was diluted with methylene chloride, theresultant organic layer was separated, washed with a saturated aqueoussolution of sodium hydrogencarbonate and saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure to obtain crude ethyl(1R*,3S*,4S*)-3-[(tert-butoxycarbonyl)amino]-4-[(methanesulfonyl)oxy]cyclohexane-carboxylate.

The product obtained above was dissolved in N,N-dimethylformamide (100ml), and sodium azide (18 g) was added at room temperature. The mixturewas heated to 75° C. and stirred for 12 hours. The solvent wasconcentrated to about 1/3, and the residue was diluted with water andethyl acetate to conduct stirring for 3 minutes. The resultant organiclayer was separated, washed with saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane=1:4) to obtainthe title compounds [(1R*,3S*,4R*)-form (6.74 g) and (1R*,3S*,4S*)-form(1.32 g)].

(1R*,3S*,4R*)-form:

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.45 (9H, s), 1.38-2.33 (6H,m), 2.57-2.68 (1H, m), 3.77-4.20 (4H, m), 4.63 (1H, br.s).

(1R*,3S*,4S*)-form:

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.53-2.30 (6H,m), 2.50-2.65 (1H, m), 3.42-3.72 (2H, m), 4.15 (2H, q. J=7.1 Hz), 4.67(1H, br.s).

Referential Example 90 Ethyl(1R*,3S*,4R*)-4-amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

Ethyl(1R*,3S*,4R*)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate(5.4 g) obtained in Referential Example 89 was dissolved in a mixedsolvent of ethanol (10 ml) and ethyl acetate (10 ml), and a catalyticamount of 10% palladium on carbon was added to stir the mixture at roomtemperature for 20 hours in a hydrogen atmosphere. After insolublematter was removed by filtration, the solvent was distilled off underreduced pressure to obtain the title compound (4.7 g).

Referential Example 91 Ethyl(1R*,3S*,4R*)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound (4.62 g) obtained in Referential Example 90 was dissolvedin methylene chloride (50 ml), 5-chloroindole-2-carboxylic acid (3.63g), 1-hydroxybenzotriazole monohydrate (2.43 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45 g)were added at room temperature, and the mixture was stirred for 12hours. After 0.1N hydrochloric acid was added, and the mixture wasextracted with methylene chloride, the resultant organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate andsaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(ethyl acetate:hexane=2:3) to obtain the title compound (5.3 g).

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.43 (9H, s), 1.35-2.46 (7H,m), 3.91-4.02 (1H, m), 4.10-4.22 (2H, m), 4.79 (1H, br.s), 6.79 (1H, s),7.18-7.40 (2H, m), 7.59 (1H, s), 8.00 (1H, br.s), 9.13 (1H, br.s).

Referential Example 92 Ethyl(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylate

(1S,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org. Chem., 1996,Vol. 61, p. 8687) (89.3 g) was suspended in ethanol (810 ml), a 2Naqueous solution (213 ml) of sodium hydroxide was added, and the mixturewas then stirred at room temperature for 3 hours. After the solvent wasdistilled off under reduced pressure, and water was added to the residueto conduct extraction with methylene chloride, the extract was driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=17:3) to obtain the title compound(41.3 g).

[α]_(D) ²⁵=−58° (C=1.0, chloroform).

Referential Example 93 Ethyl(1S,3R,4R)-3-azido-4-hydroxycyclohexanecarboxylate

The compound (41 g) obtained in Referential Example 92 was dissolved inN,N-dimethylformamide (300 ml), ammonium chloride (19.3 g) and sodiumazide (23.5 g) were successively added at room temperature, and themixture was then stirred at 76° C. for 13 hours. The reaction mixturewas filtered, the filtrate was concentrated, the product previouslycaptured by the filter was put in the residue, and water was added todissolve the collected product. The solution was extracted with ethylacetate. The resultant organic layer was washed with water and saturatedaqueous solution of sodium chloride and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain the title compound (51.5 g).

[α]_(D) ²⁵=+8° (C=1.0, chloroform).

Referential Example 94 Ethyl(1S,3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxycyclohexanecarboxylate

The compound (51.2 g) obtained in Referential Example 93 anddi-tert-butyl dicarbonate (68.1 g) were dissolved in ethyl acetate (1000ml), 5% palladium on carbon (5.0 g) was added, and the mixture wasstirred overnight at room temperature under a hydrogen pressure of 7kg/cm². After insoluble matter was removed by filtration, the solventwas distilled off under reduced pressure, the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=4:1→3:1), andhexane was added to solidify it to obtain the title compound (46.9 g).

[α]_(D) ²⁵=+25° (C=1.0, chloroform)

Referential Example 95 Ethyl(1S,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylateand ethyl(1S,3R,4R)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound (53.5 g) obtained in Referential Example 94 andtriethylamine (130 ml) were dissolved in methylene chloride (500 ml),and methanesulfonyl chloride (42 ml) was added dropwise over 20 minutesunder cooling at −10° C. to −15° C. After stirring for 20 minutes at thesame temperature, the mixture was heated to room temperature over 2hours. The reaction mixture was cooled to 0° C., 0.5N hydrochloric acid(800 ml) was added dropwise, and the mixture was extracted withmethylene chloride. The resultant organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtaincrude ethyl(1S,3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate.

The crude product obtained above was dissolved in N,N-dimethylformamide(335 ml), and sodium azide (60.5 g) was added to stir the mixture at 67°C. to 75° C. for 16 hours. The reaction mixture was filtered, thefiltrate was concentrated to distill off 250 ml of the solvent, theproduct captured by the filter was put in the residue, and the collectedproduct was dissolved in water and extracted with ethyl acetate. Theresultant organic layer was washed with saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane=1:4) toobtain the title compounds [(1S,3R,4S)-form (18.4 g) and (1S,3R,4R)-form(3.3 g)].

(1S,3R,4S)-form: [α]_(D) ²⁵=+62° (C=1.0, chloroform).

(1S,3R,4R)-form: [α]_(D) ²⁵=−19° (C=1.0, chloroform).

Referential Example 96 Ethyl(1S,3R,4S)-4-Amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound (4.0 g) obtained in Referential Example 95 was dissolved ina mixed solvent of ethanol (150 ml) and ethyl acetate (150 ml), and 5%palladium on carbon (0.5 g) was added to stir the mixture at roomtemperature for 17 hours in a hydrogen atmosphere (5 kg/cm²). Afterinsoluble matter was removed by filtration, the solvent was distilledoff under reduced pressure to obtain the title compound (4.2 g).

Referential Example 97 Ethyl(1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound (4.2 g) obtained in Referential Example 96 was dissolved inmethylene chloride (50 ml), 5-chloroindole-2-carboxylic acid (3.33 g),1-hydroxybenzotriazole monohydrate (2.52 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.15 g)were added at room temperature, and the mixture was stirred for 12hours. After 0.1N hydrochloric acid was added to the reaction mixture,and the mixture was extracted with methylene chloride, the resultantorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:1) to obtain thetitle compound (4.36 g).

[α]_(D) ²⁵=−27° (C=1.0, chloroform).

Referential Example 98 Ethyl(1R*,3S*,4R*)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained from the compound obtained inReferential Example 90 and the compound obtained in Referential Example10 in a similar manner to Referential Example 91.

Referential Example 99 Benzyl 3-cyclohexene-1-carboxylate

(±)-3-Cyclohexene-1-carboxylic acid (50 g) was dissolved inN,N-dimethylformamide (550 ml), and triethylamine (170 ml) and benzylbromide (61 ml) were added under ice cooling to stir the mixture at roomtemperature for 12 hours. Water was added, extraction was conducted withethyl acetate, and the resultant organic layer was washed with saturatedaqueous solution of sodium chloride and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(hexane:ethyl acetate=3:1) to obtain the title compound (70.8 g).

¹H-NMR (CDCl₃) δ: 1.66-1.76 (1H, m), 2.00-2.13 (3H, m), 2.27-2.29 (2H,m), 2.58-2.65 (1H, m), 5.13 (2H, s), 5.66 (2H, br.s), 7.29-7.38 (5H, m).

Referential Example 100 Benzyl(1R*,3S*,6S*)-7-oxabicyclo[4.1.0]heptane-3-carboxylate

The compound (40 g) obtained in Referential Example 99 was dissolved inmethylene chloride (500 ml), and m-chloroperbenzoic acid (86 g) wasadded under ice cooling to stir the mixture for 2 hours. After a 10%aqueous solution of sodium thiosulfate was added to conduct stirring for20 minutes, an organic layer was separated, washed with a saturatedaqueous solution of sodium hydrogencarbonate and saturated aqueoussolution of sodium chloride and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:9) to obtain the title compound (23.4 g) and benzyl(1R*,3R*,6S*)-7-oxabicyclo[4.1.0]heptane-3-carboxylate (12.1 g).

¹H-NMR (CDCl₃) δ: 1.39-1.49 (1H, m), 1.75-1.82 (1H, m), 1.90-2.04 (3H,m), 2.30 (1H, dd, J=14.9, 4.9 Hz), 2.54-2.61 (1H, m), 3.12-3.14 (1H, m),3.22-3.24 (1H, m), 5.12 (2H, s), 7.30-7.39 (5H, m).

MS (FAB) m/z: 233 (M+H)⁺.

Referential Example 101 Benzyl(1R*,3S*,4S*)-4-azido-3-hydroxycyclohexanecarboxylate

The compound (52.3 g) obtained in Referential Example 100 was dissolvedin N,N-dimethylformamide (1000 ml), ammonium chloride (21.9 g) andsodium azide (18.1 g) were added, and the mixture was heated to 70° C.and stirred for 24 hours. The solvent was distilled off under reducedpressure, and water was added to conduct extraction with ethyl acetate.The resultant organic layer was washed with saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (61.8 g).

¹H-NMR (CDCl₃) δ: 1.51-1.66 (2H, m), 1.91-1.98 (1H, m), 2.07-2.10 (1H,m), 2.27-2.32 (1H, m), 2.51-2.52 (1H, m), 2.81-2.86 (1H, m), 3.30-3.36(1H, m), 3.70-3.75 (1H, m), 5.13 (2H, s), 7.30-7.39 (5H, m).

Referential Example 102 Benzyl(1R*,3S*,4S*)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylate

The compound (5.27 g) obtained in Referential Example 101 was dissolvedin tetrahydrofuran (25 ml), and triphenylphosphine (5.53 g) and water(0.55 ml) were added to stir the mixture at room temperature for 20hours. Ditert-butyl dicarbonate (4.82 g) was added to the reactionmixture to continue stirring for additional 2 hours. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=2:1) to obtainthe title compound (6.22 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.59-1.66 (2H, m), 1.88-2.00 (2H, m),2.29-2.32 (1H, m), 2.80-2.85 (1H, m), 3.02 (1H, br.s), 3.42 (1H, br.s),3.59-3.65 (1H, m), 4.56 (1H, br.s), 5.12 (2H, q, J=12.5 Hz), 7.30-7.38(5H, m).

MS (FAB) m/z: 350 (M+H)⁺.

Referential Example 103 Methyl(1R*,3S*,4S*)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylate

The compound (2.54 g) obtained in Referential Example 102 was dissolvedin ethyl acetate (15 ml), and a catalytic amount of 10% palladium oncharcoal was added to the solution. The mixture was stirred in ahydrogen stream at room temperature for 20 hours. After the catalyst wasfiltered off, the filtrate was concentrated under reduced pressure togive(1R*,3S*,4S*)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylicacid as an colorless oil. The oil was dissolved in a mixture of methanol(8 ml) and toluene (15 ml), to which a 2N hexane solution (10 ml) oftrimethylsilyldiazomethane was added under ice cooling, and theresulting mixture was stirred for 30 minutes at room temperature. Afterremoval of the solvent under reduced pressure, the resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=1:1) to obtain the title compound (1.82 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.36-2.32 (7H, m), 2.74-2.82 (1H, m),3.04 (1H, br.s), 3.33-3.47 (1H, m), 3.55-3.65 (1H, m), 3.68 (3H, s),4.56 (1H, br.s).

MS (FAB) m/z: 274 (M+H)⁺.

Referential Example 104 Methyl(1R*,3R*,4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylateand methyl(1R*,3S*,4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound (1.81 g) obtained in Referential Example 103 was dissolvedin methylene chloride (36 ml), and triethylamine (4.6 ml) andmethanesulfonyl chloride (1.63 ml) were added at −78° C. After 30minutes, the mixture was heated to 0° C. and stirred for 30 minutes. 1NHydrochloric acid was added, extraction was conducted with methylenechloride, and the resultant organic layer was washed with saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtaincrude methyl(1R*,3S*,4S*)-4-[(tert-butoxycarbonyl)amino]-3-[(methylsulfonyl)oxy]-cyclohexanecarboxylate.

The crude product obtained above was dissolved in N,N-dimethylformamide(23 ml), sodium azide (1.29 g) was added, and the mixture was heated to70° C. and stirred for 12 hours. Water was added to the reactionmixture, extraction was conducted with ethyl acetate, and the resultantorganic layer was washed with saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified byflash column chromatography on silica gel (ethyl acetate:hexane=3:17) toobtain methyl(1R*,3S*,4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate(85 mg) and methyl(1R*,3R*,4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate(590 mg).

(1R*,3R*,4S*)-form: ¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.35-2.35 (7H, m),2.45-2.55 (1H, m), 3.73 (3H, s), 3.67-3.84 (2H, m), 4.70 (1H, br.s).

MS (FAB) m/z: 299 (M+H)⁺.

(1R*,3S*,4S*)-form: ¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.56-2.25 (7H, m),2.68-2.80 (1H, m), 3.70 (3H, s), 3.48-3.68 (2H, m), 4.56 (1H, br.s).

MS (FAB) m/z: 299 (M+H)⁺.

Referential Example 105 Methyl(1R*,3R*,4S*)-3-amino-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The (1R*,3R*,4S*)-compound (230 mg) obtained in Referential Example 104was dissolved in ethyl acetate (8 ml), and a catalytic amount of 10%palladium on carbon was added to stir the mixture at room temperaturefor 20 hours in a hydrogen atmosphere. Insoluble matter was removed byfiltration, and the filtrate was concentrated under reduced pressure toobtain the title compound (220 mg).

Referential Example 106 Methyl(1R*,3R*,4S*)-4-[(tert-butoxycarbonyl)amino-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained from the compound obtained inReferential Example 105 and the compound obtained in Referential Example10 in a similar manner to Referential Example 91.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.53-1.95 (5H, m), 2.17-2.24 (1H, m),2.50 (3H, s), 2.50-2.53 (1H, m), 2.80-2.96 (4H, m), 3.67 (3H, s),3.69-3.74 (1H, m), 4.10 (2H, br.s), 4.88 (1H, br.s).

MS (FAB) m/z: 453 (M+H)⁺.

Referential Example 107 Methyl(1R*,3R*,4S*)-4-[(tert-butoxycarbonyl)amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained from the compound obtained inReferential Example 105 in a similar manner to Referential Example 91.

¹H-NMR (CDCl₃) δ: 1.33 (9H, s), 1.42-2.47 (6H, m), 2.78-2.88 (1H, m),3.70 (3H, s), 3.86-4.15 (2H, m), 4.65-4.75 (1H, m), 6.86 (1H, br.s),7.18-7.38 (2H, m), 7.57-7.61 (1H, m), 8.32 (1H, br.s).

MS (ESI) m/z: 450 (M+H)⁺.

Referential Example 108 Benzyl(1S,3R,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylate

1) Benzyl (1R)-3-cyclohexene-1-carboxylate was obtained from(1R)-3-cyclohexene-1-carboxylic acid (J. Am. Chem. Soc., 1978, Vol. 100,p. 5199) in a similar manner to Referential Example 99.

2) The title compound was obtained from the above-described product in asimilar manner to Referential Example 100.

MS (FAB) m/z: 233 (M+H)⁺.

Referential Example 109 Benzyl(1R,3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylate

1) Benzyl (1R,3S,4S)-4-azido-3-hydroxycyclohexanecarboxylate wasobtained from the compound obtained in Referential Example 108 in asimilar manner to Referential Example 101.

2) The title compound was obtained from the above-described product in asimilar manner to Referential Example 102.

MS (FAB) m/z: 350 (M+H)⁺.

Referential Example 110 Benzyl(1R,3R,4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The title compound was obtained from the compound obtained inReferential Example 109 in a similar manner to Referential Example 104.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.52-1.66 (2H, m), 1.83-2.01 (3H, m),2.20-2.28 (1H, m), 2.51-2.54 (1H, m), 3.77 (2H, br.s), 4.70 (1H, br.s),5.15 (2H, ABq, J=12.2 Hz), 7.33-7.38 (5H, m).

MS (FAB) m/z: 375 (M+H)⁺.

Referential Example 111 Methyl(1R,3R,4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound (3.5 g) obtained in Referential Example 110 was dissolvedin tetrahydrofuran (130 ml) and water (16 ml), and lithium hydroxide(291 mg) was added under ice cooling. After 10 minutes, the mixture washeated to room temperature to continue stirring. After 20 hours, thereaction was stopped, the solvent was distilled off under reducedpressure, and the resultant residue was subjected to columnchromatography on silica gel (methanol:methylene chloride=1:20) toobtain(1R,3R,4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylicacid (3.34 g) as a pale yellow oil. This product was dissolved inmethanol (18 ml) and toluene (64 ml), a 2N hexane solution (6.1 ml) oftrimethylsilyldiazomethane was added under ice cooling. After 10minutes, the mixture was heated to room temperature and stirred for 2hours. After the solvent was distilled off under reduced pressure, theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:4) to obtain the title compound (3.35 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.57-1.63 (2H, m) 1.82-1.85 (1H, m),1.95-1.99 (2H, m), 2.20-2.28 (1H, m), 2.48-2.51 (1H, m), 3.73 (3H, s),3.78 (2H, br.s), 4.70-4.72 (1H, m).

MS (FAB) m/z: 299 (M+H)⁺.

Referential Example 112 Methyl(1R,3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

1) Methyl(1R,3R,4S)-3-amino-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylatewas obtained from the compound obtained in Referential Example 111 in asimilar manner to Referential Example 105.

2) The title compound was obtained from the above-described product andthe compound obtained in Referential Example 10 in a similar manner toReferential Example 106.

MS (FAB) m/z: 453 (M+H)⁺.

Referential Example 113 tert-Buthyl(1R*,2S*,5S*)-5-aminocarbonyl-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate

The compound (590 mg) obtained in Referential Example 91 was dissolvedin a mixed solvent of ethanol (3 ml) and tetrahydrofuran (6 ml), a 1Naqueous solution (2.5 ml) of sodium hydroxide was added at roomtemperature, and the mixture was stirred for 12 hours. The solvent wasdistilled off to obtain sodium(1R*,3S*,4R*)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylate.This product was suspended in N,N-dimethylformamide (4 ml),di-tert-butyl dicarbonate (654 mg) and ammonium hydrogencarbonate (1 g)were added at room temperature, and the mixture was stirred for 18hours. The solvent was distilled off under reduced pressure, and waterwas added to conduct extraction with chloroform. The resultant organiclayer was washed with saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (methylene chloride:methanol=47:3) toobtain the title compound (82 mg).

MS (ESI) m/z: 435 (M+H)⁺.

Referential Example 114 Benzyl(1R,6S)-6-{[(benzyloxy)carbonyl]amino}-3-cyclohexen-1-ylcarbamate

4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was dissolved in a mixedsolvent of water (20 ml) and acetonitrile (20 ml), and benzylchloroformate (7.66 ml) and potassium carbonate (14.9 g) were added, andthe mixture was stirred at room temperature for 3 days. The reactionmixture was poured into water to conduct extraction with methylenechloride. The resultant organic layer was washed with saturated aqueoussolution of sodium chloride, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel (methylene chloride)to obtain the title compound (8.22 g).

¹H-NMR (CDCl₃) δ: 2.03 (2H, m), 2.53 (2H, d, J=17.1 Hz), 3.77 (2H, m),5.03 (2H, q, J=12.3 Hz), 5.09 (2H, q, J=12.3 Hz), 5.59 (2H, s), 7.32(10H, m).

MS (ESI) m/z: 381 (M+H)⁺.

Referential Example 115 Benzyl(1R*,2S*)-2-{[(benzyloxy)carbonyl]amino}-5-hydroxycyclohexylcarbamate

The compound (10 g) obtained in Referential Example 114 was dissolved inabsolute tetrahydrofuran (70 ml), borane-dimethyl sulfide complex (7.4ml) was added at 0° C., and the mixture was gradually heated to roomtemperature and stirred for 14 hours. Ice was added to the reactionmixture to decompose excessive borane, and a 1N aqueous solution (80 ml)of sodium hydroxide and 30% aqueous hydrogen peroxide (80 ml) were addedto stir the mixture for 1 hour as it is. The reaction mixture wasextracted with ethyl acetate, and the resultant organic layer was washedwith saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (ethyl acetate:hexane 2:1) to obtain the title compound (9.2g).

¹H-NMR (CDCl₃) δ: 1.98 (1H, m), 2.08 (1H, m), 2.30 (1H, m), 3.43 (2H,m), 3.73 (1H, m), 5.06 (6H, m), 7.32 (10H, s).

MS (ESI) m/z: 399 (M+H)⁺.

Referential Example 116 Benzyl(1R*,2S*)-2-{[(benzyloxy)carbonyl]amino}-5-oxocyclohexylcarbamate

Dimethyl sulfoxide (8.2 ml) was added to a solution of oxalyl chloride(9.9 ml) in methylene chloride (90 ml) at −60° C., and a solution of thecompound (9.2 g) obtained in Referential Example 115 in tetrahydrofuran(90 ml) was added to the mixture at a time. After 1 hour, thetemperature of the mixture was raised to −40° C., and triethylamine (26ml) was added at a time. The mixture was heated to room temperature asit is, and stirred for 3 hours. The reaction mixture was poured intowater and extracted with methylene chloride. The resultant organic layerwas washed with saturated aqueous solution of sodium chloride and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:1) to obtain the title compound(8.0 g).

¹H-NMR (CDCl₃) δ: 2.27-2.43 (4H, m), 2.78 (1H, dd, J=14.4, 3.9 Hz), 3.86(2H, m), 5.08 (4H, m), 5.22 (2H, m), 7.32 (10H, m).

MS (ESI) m/z: 397 (M+H)⁺.

Referential Example 117 Benzyl(1R*,2S*)-2-{[(benzyloxy)carbonyl]amino}-5,5-dimethoxycyclohexylcarbamate

The compound (3.89 g) obtained in Referential Example 116 was dissolvedin a mixed solvent of methanol (15 ml) and tetrahydrofuran (15 ml),2,2-dimethoxypropane (10.7 ml) and p-toluenesulfonic acid (187 mg) wereadded, and the mixture was stirred at room temperature for 3 hours. Thesolvent was concentrated, and a saturated aqueous solution of sodiumhydrogencarbonate was added to conduct extraction with ethyl acetate.After the resultant organic layer was washed with saturated aqueoussolution of sodium chloride and dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (ethylacetate:hexane=1:2) to obtain the title compound (3.54 g).

¹H-NMR (CDCl₃) δ: 1.30-1.41 (4H, m), 1.93 (1H, m), 2.38 (1H, m), 3.19(6H, s), 3.46 (1H, m), 3.59 (1H, m), 5.03 (2H, q, J=12.5 Hz), 5.09 (2H,q, J=12.5 Hz), 7.32 (10H, s).

Referential Example 118N-[(1R*,2S*)-2-Amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamideandN-[(1R*,2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide

The compound (1.45 g) obtained in Referential Example 117 was dissolvedin methanol (12 ml), and 10% palladium on carbon (290 mg) was added tostir the mixture at room temperature for 20 hours in a hydrogenatmosphere. 10% Palladium on carbon (290 mg) and methanol (10 ml) wereadditionally added to stir the mixture for 8 hours. The reaction mixturewas filtered through Celite, and mother liquor was concentrated, and theresidue was dissolved in N,N-dimethylformamide (10 ml).5-Chloroindole-2-carboxylic acid (320 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377 mg),1-hydroxybenzotriazole monohydrate (301 mg) and N-methylmorpholine (360ml) were added, and the mixture was stirred at room temperature for 14hours. The reaction mixture was poured into an aqueous solution ofsodium hydrogencarbonate and extracted with ethyl acetate. The resultantorganic layer was washed with saturated aqueous solution of sodiumchloride and then dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure, and the residue was isolated andpurified by preparative thin-layer chromatography on silica gel(methylene chloride:methanol=93:7) to obtainN-[(1R*,2S*)-2-amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide(orN-[(1R*,2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide)(98 mg) andN-[(1R*,2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide(orN-[(1R*,2S*)-2-amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide)(105 mg).N-[(1R*,2S*)-2-Amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide

¹H-NMR (CDCl₃) δ: 1.45-1.50 (2H, m), 2.06-2.10 (2H, m), 2.34 (1H, d,J=13.1 Hz), 2.78 (1H, dt, J=2.9, 13.1 Hz), 3.18 (3H, s), 3.23 (3H, s),3.75-3.77 (1H, m), 6.24 (1H, d, J=8.3 Hz), 6.79 (1H, s), 7.23 (1H, dd,J=8.8, 2.0 Hz), 7.35 (1H, d, J=8.8 Hz), 7.60 (1H, d, J=8.8 Hz), 9.53(1H, br.s).

MS (ESI) m/z: 352 (M+H)⁺.

N-[(1R*,2S*)-2-Amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide

¹H-NMR (CDCl₃) δ: 1.83-1.87 (1H, m), 1.97-2.01 (1H, m), 2.39 (1H, br,J=13.2 Hz), 2.86-2.90 (1H, m), 3.22-3.28 (10H, m), 4.00-4.02 (1H, m),6.77 (1H, s), 7.23 (1H, d, J=8.5 Hz), 7.37 (1H, d, J=8.5 Hz), 7.61 (1H,s), 9.49 (1H, br.s).

MS (ESI) m/z: 352 (M+H)⁺.

Referential Example 119 Benzyl(7R*,8S*)-7-{[(benzyloxy)carbonyl]amino}-1,4-dioxaspiro[4.5]dec-8-ylcarbamate

The compound (4.0 g) obtained in Referential Example 116 was dissolvedin absolute tetrahydrofuran (30 ml), and ethylene glycol (5.6 ml) andp-toluenesulfonic acid (192 mg) were added to stir the mixture at roomtemperature for 17 hours. The reaction mixture was poured into asaturated aqueous solution of sodium hydrogencarbonate and extractedwith ethyl acetate. The resultant organic layer was washed withsaturated aqueous solution of sodium chloride and then dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (ethyl acetate:hexane=1:1) to obtain the title compound (4.23g).

¹H-NMR (CDCl₃) δ: 6.65-1.71 (4H, m), 2.00 (1H, m), 2.11 (1H, m), 3.49(1H, m), 3.73 (1H, m), 3.93 (4H, s), 5.03 (2H, q, J=12.2 Hz), 5.08 (2H,q, J=12.2 Hz), 7.32 (10H, s).

MS (ESI) m/z: 441 (M+H)⁺.

Referential Example 120N-[(7R*,8S*)-7-Amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamideandN-[(7R*,8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide

N-[(7R*,8S*)-7-Amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide(orN-[(7R*,8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide)andN-[(7R*,8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide(orN-[(7R*,8S*)-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide)were obtained from the compound obtained in Referential Example 119 in asimilar manner to Referential Example 118.N-[(7R*,8S*)-7-Amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide(orN-[(7R*,8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide

¹H-NMR (CDCl₃) δ: 1.68-1.81 (4H, m), 2.11 (2H, m), 2.87 (1H, td, J=3.9,11.2 Hz), 3.77 (1H, m), 3.97 (4H, s), 6.27 (1H, d, J=7.6 Hz), 6.80 (1H,s), 7.24 (1H, d, J=9.0 Hz), 7.35 (1H, d, J=9.0 Hz), 7.61 (1H, s), 9.47(br.s, 1H).

MS (ESI) m/z: 350 (M+H)⁺.

N-[(7R*,8S*)-8-Amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide(orN-[(7R*,8S*)-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide)

¹H-NMR (CDCl₃) δ: 1.65 (2H, m), 1.88 (1H, m), 1.96 (1H, m), 2.31 (1H,dd, J=12.9, 3.2 Hz), 2.96 (1H, m), 3.98 (1H, m), 4.02 (4H, s), 4.12 (1H,m), 6.77 (1H, s), 7.06 (1H, br.s), 7.23 (1H, dd, J=8.8, 2.0 Hz), 7.37(1H, d, J=8.8 Hz), 7.62 (1H, d, J=2.0 Hz), 9.49 (1H, br.s).

MS (ESI) m/z: 350 (M+H)⁺.

Referential Example 121 tert-Butyl(1R,6S)-6-[(tert-butoxycarbonyl)amino]-3-cyclohexene-1-ylcarbamate

cis-4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was dissolved in amixed solvent of water (40 ml) and acetonitrile (40 ml), anddi-tert-butoxy carbonate (11.8 g) and triethylamine (12 ml) were added,and the mixture was stirred at room temperature for 4.5 hours. Thereaction mixture was poured into water to conduct extraction withmethylene chloride, and the resultant methylene chloride layer waswashed with saturated aqueous solution of sodium chloride and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:4) to obtain the title compound(6.12 g).

¹H-NMR (CDCl₃) δ: 1.44 (18H, s), 1.98 (2H, dd, J=9.3, 15.9 Hz), 2.48(2H, br.d, J=15.9 Hz), 3.66 (2H, br.s), 4.88 (2H, br.s), 5.58 (2H, d,J=2.7 Hz).

Referential Example 122 tert-Butyl(1R*,2S*)-2-[(tert-butoxycarbonyl)amino]-5-hydroxycyclohexylcarbamate(mixture of stereoisomers)

The compound (6.1 g) obtained in Referential Example 121 was dissolvedin absolute tetrahydrofuran (40 ml), and borane-dimethyl sulfide complex(2.22 ml) was added under ice cooling. The mixture was stirred for 16hours while gradually heating the mixture to room temperature as it is.Ice was added to the reaction mixture, and a 1N aqueous solution ofsodium hydroxide and 30% aqueous hydrogen peroxide (50 ml) were added tostir the mixture at room temperature for 2 hours as it is. The reactionmixture was extracted with ethyl acetate, and the resultant organiclayer was washed with saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:2→2:1) to obtain the titlecompound (6.1 g).

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.43 (9H, s), 1.83-1.67 (5H, m), 2.15(1H, m), 2.22 (1H, s), 3.34 (1H, m), 3.78 (1H, m), 4.15 (1H, s), 4.98(1H, q, J=9.0 Hz), 5.02 (1H, q, J=9.0 Hz).

MS (ESI) m/z: 331 (M+H)⁺.

Referential Example 123 tert-Butyl(1R*,2S*)-2-[(tert-butoxycarbonyl)amino]-5-oxocyclohexylcarbamate

Oxalyl chloride (8.2 ml) and dimethyl sulfoxide (6.8 ml) were dissolvedin methylene chloride (100 ml) at −60° C., and a solution of thecompound (mixture of stereoisomers) (6.32 g) obtained in ReferentialExample 122 in tetrahydrofuran (80 ml) was added at a time, and themixture was stirred for 1 hour. The temperature of the mixture wasraised to −40° C., and triethylamine (21 ml) was added. The mixture washeated to room temperature. After 3 hours, the reaction mixture waspoured into water and extracted with methylene chloride. The resultantorganic layer was washed with saturated aqueous solution of sodiumchloride and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane=1:1) to obtainthe title compound (3.8 g).

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.44 (9H, s), 2.24-2.36 (3H, m),2.39-2.44 (2H, m), 2.75 (1H, dd, J=14.6, 2.9 Hz), 3.66-3.81 (2H, m),4.95-4.90 (1H, m), 4.97-5.03 (1H, m).

MS (ESI) m/z: 329 (M+H)⁺.

Referential Example 124 tert-Butyl(1R*,2S*)-2-[(tert-butoxycarbonyl)amino]-5-(methoxyimino)cyclohexylcarbamate

The compound (1.5 g) obtained in Referential Example 123 was dissolvedin methanol (30 ml), and O-methylhydroxyamine hydrochloride (572 mg) andpyridine (737 ml) were added to stir the mixture at room temperature for17 hours. After the reaction mixture was concentrated, water was addedto conduct extraction with ethyl acetate. The resultant organic layerwas washed with saturated aqueous solution of sodium chloride and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:4) to obtain the title compound(1.52 g).

¹H-NMR (CDCl₃) δ: 1.44 (18H, s), 1.64 (1H, m), 2.16 (2H, m), 2.44 (1H,m), 3.45-3.63 (3H, m), 3.82 (3H, s), 4.93 (1H, m).

MS (ESI) m/z: 358 (M+H)⁺.

Referential Example 125 tert-Butyl(1R*,2S*)-2-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(diphenyl)silyl]oxy}cyclohexylcarbamate(Stereoisomer A)

The title compound was obtained from the compound (mixture ofstereoisomers) obtained in Referential Example 122 in a similar mannerto Referential Example 58, and tert-butyl(1R*,2S*)-2-[(tert-butoxycarbonyl)amino]-5-hydroxycyclohexylcarbamate(Stereoisomer B) was recovered.

¹H-NMR (CDCl₃) δ: 1.03 (9H, s), 1.39 (9H, s), 1.40 (9H, s), 1.72 (1H,m), 1.86 (1H, m), 2.13 (1H, m), 3.24 (2H, m), 3.65 (1H, m), 4.83 (1H,m), 7.37 (10H, m).

Referential Example 126 Benzyl(1R*,2S*)-2-{[(benzyloxy)carbonyl]amino}-5-hydroxy-5-methylcyclohexylcarbamate

Anhydrous cerium chloride (6.4 g) was suspended in tetrahydrofuran (50ml), and the suspension was cooled to −78° C. in an argon atmosphere. Amethyllithium solution (1.14N diethyl ether solution, 22.5 ml) was addedto the suspension, and the mixture was stirred at −78° C. for 30minutes. A tetrahydrofuran solution (50 ml) of the compound (3.0 g)obtained in Referential Example 116 was added dropwise at −78° C., andthe mixture was stirred for 30 minutes. The reaction mixture was pouredinto a 3% aqueous solution (100 ml) of acetic acid, and diethyl ether(50 ml) was added to stir the mixture at room temperature for 10minutes. The reaction mixture was extracted with ethyl acetate, and theresultant organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and saturated aqueous solution of sodiumchloride and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified twiceby column chromatography on silica gel (methanol:chloroform=0:100-1:19)to obtain the title compound (Stereoisomer A) (780 mg) and the titlecompound (Stereoisomer B) (1.1 g).

Stereoisomer A:

¹H-NMR (CDCl₃) δ: 1.26 (3H, s), 1.27-2.08 (6H, m), 3.48 (1H, br.s), 3.59(1H, br.s), 5.02-5.09 (5H, m), 5.33 (1H, br.s), 7.30-7.32 (10H, s)

MS (FAB) m/z: 413 (M+H)⁺.

Stereoisomer B:

¹H-NMR (CDCl₃) δ: 1.25 (3H, s), 1.29-2.07 (6H, m), 3.39 (1H, br.s), 3.82(1H, br.s), 5.02-5.23 (6H, m), 7.30 (10H, s)

MS (FAB) m/z: 413 (M+H)⁺.

Referential Example 127 (3R*,4S*)-3,4-Diamino-1-methylcyclohexanol(Stereoisomer A)

10% Palladium on carbon (350 mg) was suspended in a methanol solution(100 ml) of the compound (Stereoisomer A) (780 mg) obtained inReferential Example 126, and the suspension was stirred for 5 hours in ahydrogen atmosphere. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. After the residue wasdissolved in methylene chloride (100 ml), and the solution was driedover anhydrous sodium sulfate, the solvent was distilled off to obtainthe title compound (Stereoisomer A) (190 mg).

¹H-NMR (CDCl₃) δ: 1.22 (3H, s), 1.25-2.48 (11H, m), 2.62 (1H, br.s),2.78 (1H, br.s).

Referential Example 128 Mixture ofN-[(1R*,2S*)-2-Amino-4-hydroxy-4-methylcyclohexyl]-5-chloroindole-2-carboxamide(Stereoisomer A) andN-[(1R*,2S*)-2-amino-5-hydroxy-5-methylcyclohexyl]-5-chloroindole-2-carboxamide(Stereoisomer A)

The title compound was obtained from the compound (Stereoisomer A)obtained in Referential Example 127 and 5-chloroindole-2-carboxylic acidin a similar manner to Referential Example 59.

¹H-NMR (CDCl₃) δ: 1.32 (3H, s), 1.34-2.29 (6H, m), 4.42-4.70 (4H, br),7.13 (2H, s), 7.50 (2H, s), 8.00 (1H, s), 11.0 (1H, br).

Referential Example 129 tert-Butyl(1R*,2R*,5S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)cyclohexylcarbamate

1) Ethyl(1R*,3S*,4S*)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylatewas obtained from the (1R*,3S*,4S*)-form obtained in Referential Example89 in a similar manner to the process described in Referential Examples90 and 91.

¹H-NMR (CDCl₃) δ: 1.22-1.72 (6H, m), 2.15-2.28 (2H, m), 2.41-2.49 (1H,m), 2.85 (1H, brs), 3.62-3.75 (1H, m), 3.78-3.92 (1H, m), 4.12-4.28 (2H,m), 4.56-4.63 (1H, m), 6.88 (1H, brs), 7.20 (1H, dd, J=8.8 and 2.0 Hz),7.33 (1H, d, J=8.8 Hz), 7.52-7.57 (1H, m), 7.59 (1H, d, J=2.0 Hz), 9.24(1H, s).

MS (ESI) m/z: 464 (M+H)⁺.

2) The product (735 mg) obtained above was dissolved in methylenechloride (10 ml), a 1N hexane solution (5 ml) of diisobutylaluminiumhydride was added at −78° C., and the mixture was stirred for 3 hoursand then 30 minutes at 0° C. A saturated aqueous solution of ammoniumchloride was added at −78° C., the mixture was extracted with methylenechloride, and the resultant organic layer was washed with a saturatedaqueous solution of sodium bicarbonate and saturated aqueous solution ofsodium chloride and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methylenechloride:methanol=19:1) to obtain the title compound (480 mg).

¹H-NMR (CDCl₃) δ: 1.20-2.30 (7H, m), 3.60-3.86 (4H, m), 4.64 (1H, br.s),6.87 (1H, s), 7.20-7.48 (3H, m), 9.15 (1H, br.s).

MS (ESI) m/z: 422 (M+H)⁺.

Referential Example 130(1R*,3R*,6S*)-3-(Methoxymethyl)oxabicyclo[4.1.0]heptane

1) (1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (2.8 g) wasdissolved in a mixed solvent of tetrahydrofuran (27 ml) and water (3ml), concentrated hydrochloric acid (0.1 ml) was added, and the mixturewas heated under reflux for 1 hour. The solvent was distilled off underreduced pressure to obtain(1R*,3R*,4R*)-3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g) as acolorless solid.

2) The product (3.22 g) obtained by the reaction described above wasdissolved in tetrahydrofuran (50 ml), borane-dimethyl sulfide complex (2M tetrahydrofuran solution, 47 ml) was added under ice cooling, and themixture was stirred at room temperature for 12 hours. The solvent wasdistilled off under reduced pressure, the residue was dissolved inisopropanol (10 ml), a 1N aqueous solution (12 ml) of sodium hydroxidewas added, and the mixture was stirred for 12 hours. After the solventwas concentrated to about 1/5, the reaction mixture was diluted withwater and methylene chloride to stir it for 10 minutes. An organic layerwas separated, successively washed with a saturated aqueous solution ofammonium chloride and saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:2) to obtain(1R*,3R*,6S*)-7-oxabicyclo[4.1.0]hept-3-ylmethanol (1.25 g) as acolorless oil.

3) The product (4.63 g) obtained by the reaction in 2) was dissolved intetrahydrofuran (50 ml), potassium bis(trimethylsilyl)amide (0.5Ntoluene solution, 80 ml) was added to the solution at −78° C. Afterstirring at same temperature for 10 minutes, methyl iodide (2.93 ml) wasadded. After heating the mixture to 0° C., it was stirred for 1 hour,quenched with a saturated aqueous solution of ammonium chloride and thendiluted with diethyl ether. An organic layer was separated, washed withsaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:4) to obtain the title compound (3.7 g).

¹H-NMR (CDCl₃) δ: 0.89-1.63 (5H, m), 1.80-2.05 (2H, m), 1.89-3.06 (4H,m), 3.16 (3H, s).

Referential Example 131(1R*,2R*,4S*)-2-Azido-4-(methoxymethyl)cyclohexanol

The title compound was obtained from the compound obtained inReferential Example 130 in a similar manner to Referential Example 87.

¹H-NMR (CDCl₃) δ: 1.45-1.70 (5H, m), 1.77-1.95 (2H, m), 1.98-2.08 (1H,m), 3.30 (2H, d, J=6.8 Hz), 3.35 (3H, s), 3.45-3.65 (2H, m).

Referential Example 132 tert-Butyl(1R*,2R*,5S*)-2-hydroxy-5-(methoxymethyl)cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 131 in a similar manner to Referential Example 88.

¹H-NMR (CDCl₃) δ: 1.35-2.01 (16H, m), 3.05 (1H, br.s), 3.32 (2H, d,J=7.1 Hz), 3.34 (3H, s), 3.44-3.62 (2H, m), 4.59 (1H, br.s).

Referential Example 133 tert-Butyl(1R*,2S*,5S*)-2-azido-5-(methoxymethyl)cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 132 through the methansulfonate thereof in a similarmanner to Referential Example 89.

¹H-NMR (CDCl₃) δ: 1.31-1.93 (16H, m), 3.27 (2H, d, J=6.4 Hz), 3.32 (3H,s), 3.57-3.70 (1H, m), 3.67 (1H, br.s), 3.95 (1H, br.s).

Referential Example 134 tert-Butyl(1R*,2S*,5S*)-2-amino-5-(methoxymethyl)cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 133 in a similar manner to Referential Example 90.

Referential Example 135 tert-Butyl(1R*,2S*,5S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(methoxymethyl)cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 134 and 5-chloroindole-2-carboxylic acid in asimilar manner to Referential Example 91.

¹H-NMR (CDCl₃) δ: 1.12-2.31 (16H, m), 3.14-3.30 (2H, m), 3.34 (3H, s),3.92 (1H, br.s), 4.13 (1H, br.s), 4.88 (1H, br.s), 6.82 (1H, s), 7.21(1H, br.d, J=8.8 Hz), 7.33 (1H, d, J=8.8 Hz), 7.60 (1H, s), 8.09 (1H,br.s), 9.42 (1H, br.s).

MS (ESI) m/z: 436 (M+H)⁺.

Referential Example 136 tert-Butyl(1R*,2S*,5S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 91 in a similar manner to Referential Example 129.

¹H-NMR (CDCl₃) δ: 0.78-2.30 (16H, m), 3.41-3.59 (3H, m), 3.86-3.95 (1H,m), 4.12-4.20 (1H, m), 4.82-4.91 (1H, m), 6.81 (1H, s), 7.17-7.40 (2H,m), 7.60 (1H, s), 8.03 (1H, br.s), 9.18 (1H, br.s).

MS (ESI) m/z: 422 (M+H)⁺.

Referential Example 137 tert-Butyl(1R*,2S*,5S*)-5-(azidomethyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 136 in a similar manner to Referential Example 80.

Referential Example 138 tert-Butyl 3-cyclohexen-1-ylcarbamate

3-Cyclohexene-1-carboxylic acid (25.3 g) was dissolved in tert-butanol(250 ml), triethylamine (28 ml) and diphenylphosphorylazide (43.0 ml)were added, and the mixture was stirred for 1 hour at room temperatureand 2 days at 90° C. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methylene chloride) and then repurified by columnchromatography on silica gel (hexane:ethyl acetate=20:1) to obtain thetitle compound (24.9 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.45-1.60 (1H, m), 1.80-1.90 (2H, m),2.05-2.20 (2H, m), 2.35-2.45 (1H, m), 3.78 (1H, br), 4.56 (1H, br),5.55-5.65 (1H, m), 5.65-5.75 (1H, m).

Referential Example 139 tert-Butyl(3R*,4S*)-3,4-dihydroxycyclohexylcarbamate

The compound (1.24 g) obtained in Referential Example 138 was dissolvedin a mixed solvent of acetonitrile (15 ml) and water (5 ml),N-methylmorpholine N-oxide (0.90 g) and microcapsulated 10% osmiumtetroxide (1 g) were added, and the mixture was stirred at about 80° C.for a day. After insoluble matter was removed by filtration, thefiltrate was concentrated under reduced pressure. The thus-obtainedresidue was purified by column chromatography on silica gel (methylenechloride:methanol=20:1) to obtain the title compound (1.28 g).

¹H-NMR (CDCl₃) δ: 1.15-1.30 (½H, m), 1.35-2.00 (15H, m), 2.15-2.30 (3/2H, m), 2.40-2.60 (1H, m), 3.64 (1H, br), 3.75-3.90 ( 3/2H, m), 4.00(½H, br).

MS (FAB) m/z: 232 (M+H)⁺.

Referential Example 140 tert-Butyl(3R*,4S*)-3,4-diazidocyclohexylcarbamate (Stereoisomer A andStereoisomer B)

The title compounds (Stereoisomer A and Stereoisomer B) were obtainedfrom the compound obtained in Referential Example 139 in a similarmanner to Referential Example 80.

Stereoisomer A:

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.40-1.55 (1H, m), 1.55-1.80 (3H, m),1.95-2.15 (2H, m), 3.53 (1H, m), 3.59 (1H, br), 3.80 (1H, m), 4.70 (1H,br).

Stereoisomer B:

¹H-NMR (CDCl₃) δ: 1.27 (1H, m), 1.44 (9H, s), 1.40-1.55 (1H, m),1.80-2.00 (2H, m), 2.00-2.15 (1H, m), 2.21 (1H, m), 3.48 (1H, m), 3.77(1H, br), 3.89 (1H, br), 4.34 (1H, br).

Referential Example 141 Ethyl(1S,3R,4S)-4-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound (3.10 g) obtained in Referential Example 96 was dissolvedin tetrahydrofuran (50 ml), and a saturated aqueous solution (50 ml) ofsodium hydrogencarbonate was added. After benzyloxycarbonyl chloride(1.71 ml) was added dropwise to the reaction mixture under ice cooling,the mixture was stirred at room temperature for 4 days. Ethyl acetate(200 ml) and water (200 ml) were added to the reaction mixture toconduct liquid separation. After the resultant organic layer was driedover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. Solids deposited were collected by filtration toobtain the title compound (3.24 g).

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.1 Hz), 1.29-1.44 (1H, m), 1.44 (9H,s), 1.51-1.64 (1H, m), 1.72-2.10 (4H, m), 2.27-2.43 (1H, m), 3.60-3.73(1H, m), 4.00-4.18 (3H, m), 4.62 (1H, br.s), 5.01-5.13 (2H, m), 5.26(1H, br.s), 7.27-7.38 (5H, m).

Referential Example 142(1S,3R,4S)-4-{[(Benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylicacid

The compound (620 mg) obtained in Referential Example 141 was dissolvedin tetrahydrofuran (20 ml), and an aqueous solution (10 ml) of lithiumhydroxide monohydrate (93 mg) was added to stir the mixture at roomtemperature for 16 hours. After lithium hydroxide monohydrate (217 mg)was additionally added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hours, the reaction mixture wasneutralized with 1N hydrochloric acid and extracted with methylenechloride. An organic layer was washed with saturated aqueous solution ofsodium chloride and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (600 mg).

¹H-NMR (CDCl₃) δ: 1.22-2.20 (6H, m), 1.44 (9H, s), 2.45 (1H, br.s),3.60-3.80 (1H, br), 4.09 (1H, br.s), 4.66 (1H, br.s), 5.00-5.20 (2H, m),5.26 (1H, br.s), 7.20-7.40 (5H, m).

MS (ESI) m/z: 393 (M+H)⁺.

Referential Example 143 Benzyl(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexylcarbamate

After the compound (600 mg) obtained in Referential Example 142 anddimethylamine hydrochloride (240 mg) were suspended in methylenechloride (50 ml), a proper amount of tetrahydrofuran was added to thesuspension to prepare a solution. To this solution were addedtriethylamine (0.41 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (422 mg) and 1-hydroxybenzotriazole monohydrate (338 mg),and the mixture was stirred at room temperature for 1 hour.Dimethylamine hydrochloride (480 mg) and triethylamine (0.82 ml) wereadditionally added to the reaction mixture to stir the mixture at roomtemperature for additional 18 hours. The reaction mixture was pouredinto water to separate an organic layer. After the organic layer waswashed with 1N hydrochloric acid and saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methanol:methylenechloride=3:47→2:23) to obtain the title compound (620 mg).

¹H-NMR (CDCl₃) δ: 1.20-1.50 (2H, m), 1.44 (9H, s), 1.50-2.10 (4H, m),2.60 (1H, br.t, J=11.6 Hz), 2.93 (3H, s), 3.02 (3H, s), 3.70 (1H, br.s),4.14 (1H, br.s), 4.65 (1H, br.s), 5.00-5.30 (3H, m), 7.26-7.40 (5H, m).

MS (ESI) m/z=420 (M+H)⁺.

Referential Example 144 tert-Butyl(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

10% Palladium on carbon (57 g) was added to a solution of the compound(190 g) obtained in Referential Example 143 in methanol (8000 ml), andthe mixture was stirred for 3 hours under a hydrogen pressure (7 atm).After the catalyst was removed by filtration, the filtrate wasconcentrated under reduced pressure. After toluene was added to theresidue, and the mixture was concentrated under reduced pressure, hexane(2500 ml) was added to solidify a product. The product was collected byfiltration and dried to obtain the title compound (121 g).

¹H-NMR (CDCl₃) δ: 1.20-1.77 (6H, m), 1.45 (9H, s), 2.20-2.35 (1H, br),2.63-2.74 (1H, m), 2.92 (3H, s), 3.02 (3H, s), 3.02-3.11 (2H, m),3.74-3.82 (1H, m), 4.88-5.00 (1H, br).

MS (ESI) m/z: 286 (M+H)⁺.

Referential Example 145 tert-Butyl(1R,2S,5S)-2-{[(6-chloroquinolin-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and the compound obtained in Referential Example54 in a similar manner to Referential Example 91.

¹H-NMR (CDCl₃) δ: 1.41 (9H, br), 1.50-1.70 (1H, m), 1.75-1.95 (2H, m),1.95-2.25 (3H, m), 2.65-2.80 (1H, m), 2.96 (3H, s), 3.07 (3H, s),4.15-4.30 (1H, m), 4.30-4.40 (1H, m), 4.95 (1H, br), 7.66 (1H, d, J=8.8Hz), 7.84 (1H, s), 8.00 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.6 Hz), 8.30(1H, d, J=8.6 Hz).

MS (FAB) m/z: 475 (M+H)⁺.

Referential Example 146 tert-Butyl(1R,2S,5S)-2-{[(7-chloroquinolin-3-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and the compound obtained in Referential Example57 in a similar manner to Referential Example 91.

¹H-NMR (CDCl₃) δ: 1.30-1.65 (10H, br), 1.75-1.90 (2H, m), 1.90-2.25 (3H,m), 2.65-2.90 (1H, br), 2.96 (3H, s), 3.08 (3H, s), 4.20-4.30 (1H, m),4.30-4.40 (1H, m), 4.93 (1H, br), 7.68 (1H, m), 7.90 (1H, br), 7.99 (1H,s), 8.35-8.70 (2H, m), 9.01 (1H, br).

MS (FAB) m/z: 475 (M+H)⁺.

Referential Example 1472-Bromo-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

The title compound was obtained from the compound obtained inReferential Example 8 in a similar manner to Referential Example 9.

¹H-NMR (CDCl₃) δ: 1.13 (6H, d, J=6.5 Hz), 2.86 (4H, s), 2.89-3.00 (1H,m), 3.70 (2H, s).

Referential Example 148 Lithium5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 147 in a similar manner to Referential Example 10.

¹H-NMR (DMSO-d₆) δ: 1.05 (6H, d, J=6.4 Hz), 2.68-2.70 (2H, m), 2.75-2.77(2H, m), 2.87-2.93 (1H, m), 3.66 (2H, s).

Referential Example 149 4-Nitrophenyl5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 10 and p-nitrophenol in a similar manner toReferential Example 52.

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 2.88 (2H, t, J=5.7 Hz), 3.06-3.12 (2H,m), 3.80 (2H, s), 7.46 (2H, d, J=9.3 Hz), 8.32 (2H, d, J=9.3 Hz).

MS (ESI) m/z: 320 (M+H⁺).

Referential Example 150 Benzyl 3-oxocyclobutanecarboxylate

Triethylamine (2.0 ml) and benzyl bromide (1.2 ml) were added to asolution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., Vol. 53, pp.3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml), and the mixturewas stirred at room temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate, and washed successively with 1N hydrochloricacid, a saturated aqueous solution of sodium hydrogencarbonate andsaturated saline and dried over anhydrous sodium sulfate. The solventwas then distilled off under reduced pressure, and the resultant residuewas purified by column chromatography on silica gel (ethylacetate:hexane=1:6) to obtain the title compound (886 mg).

¹H-NMR (CDCl₃) δ: 3.22-3.33 (3H, m), 3.37-3.48 (2H, m), 5.19 (2H, s),7.31-7.42 (5H, m).

MS (FAB) m/z: 205 (M+H⁺).

Referential Example 151 Benzyl 3-hydroxycyclobutanecarboxylate

Sodium borohydride (76 mg) was added to a solution of the compound (781mg) obtained in Referential Example 150 in a mixed solvent oftetrahydrofuran (10 ml) and methanol (0.5 ml) at 0° C., and the mixturewas stirred at the same temperature for 30 minutes. The reaction mixturewas diluted with ethyl acetate, and washed with a saturated aqueoussolution of sodium hydrogencarbonate and saturated aqueous solution ofsodium chloride in that order and dried over anhydrous sodium sulfate.The solvent was then distilled off under reduced pressure, and theresultant residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:2) to obtain the title compound (770 mg).

¹H-NMR (CDCl₃) δ: 2.13-2.27 (3H, m), 2.55-2.71 (3H, m), 4.14-4.23 (1H,m), 5.12 (2H, s), 7.28-7.39 (5H, m).

MS (FAB) m/z: 207 (M+H⁺).

Referential Example 152 3-Hydroxycyclobutanecarboxylic acid

10% Palladium on carbon (108 mg) was added to a solution of the compound(706 mg) obtained in Referential Example 151 in ethanol (10 ml), and themixture was stirred at room temperature for 2 hours in a hydrogenatmosphere. After the catalyst was removed by filtration through Celite,the filtrate was concentrated under reduced pressure to obtain the titlecompound (399 mg).

¹H-NMR (CD₃OD) δ: 2.00-2.21 (2H, m), 2.41-2.61 (3H, m), 4.01-4.13 (1H,m).

Referential Example 153 Benzyl 3-methoxycyclobutanecarboxylate

Methyl iodide (194 μl) and silver oxide (237 mg) were added to asolution of the compound (317 mg) obtained in Referential Example 151 inN,N-dimethylformamide (3.0 ml), and the mixture was stirred at 45° C.for 1 hour. Methyl iodide (194 μl) and silver oxide (226 mg) wereadditionally added to the reaction mixture, and the mixture was stirredat 45° C. for 16 hours. After the catalyst was removed by filtration,the filtrate was concentrated under reduced pressure, and the residuewas purified by column chromatography on silica gel (ethylacetate:hexane=1:10) to obtain the title compound (152 mg).

¹H-NMR (CDCl₃) δ: 2.14-2.24 (2H, m), 2.44-2.54 (2H, m), 2.59-2.72 (1H,m), 3.21 (3H, s), 3.73-3.81 (1H, m), 5.11 (2H, s), 7.22-7.39 (5H, m).

MS (ESI) m/z: 221 (M+H⁺).

Referential Example 154 3-Methoxycyclobutanecarboxylic acid

The title compound was obtained from the compound obtained inReferential Example 153 in a similar manner to Referential Example 152.

¹H-NMR (CDCl₃) δ: 2.17-2.27 (2H, m), 2.48-2.58 (2H, m), 2.62-2.73 (1H,m), 3.25 (3H, s), 3.76-3.86 (1H, m), 8.60-9.30 (1H, br).

Referential Example 155 Methyl 3-methoxy-2-(methoxymethyl)propionate

Sodium methoxide (1.21 g) was added to a solution of methyl2-(bromomethyl)acrylate (1.0 ml) in methanol (10 ml), and the mixturewas heated under reflux for 26 hours. After cooling, the reactionmixture was diluted with diethyl ether, and precipitate was collected byfiltration and the filtrate was concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:4) to obtain the title compound (726 mg).

¹H-NMR (CDCl₃) δ: 2.90-2.96 (1H, m), 3.34 (6H, s), 3.57 (2H, dd, J=9.3,5.9 Hz), 3.64 (2H, dd, J=9.3, 6.6 Hz), 3.73 (3H, s).

¹³C-NMR (CDCl₃) δ: 172.71, 70.31, 59.91, 46.49.

MS (ESI) m/z: 163 (M+H⁺).

Referential Example 156 Tetrahydro-2H-pyrane-4-carboxylic acid

Dimethyl tetrahydro-4H-pyrane-4,4-dicarboxylate (4.04 g) was added to20% hydrochloric acid (20 ml), and the mixture was heated under refluxfor 19 hours. Water was added to the reaction mixture to conductextraction with diethyl ether. After the resultant organic layer waswashed with saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure. After the resultant residue was solidified with hexane, theresultant solids were collected by filtration and washed to obtain thetitle compound (2.63 g).

¹H-NMR (CDCl₃) δ: 1.75-1.95 (4H, m), 2.55-2.65 (1H, m), 3.40-3.52 (2H,m), 3.93-4.05 (2H, m).

Referential Example 157 Methyl3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethylpropionate

The title compound was obtained from methyl2,2-dimethyl-3-hydroxypropionate in a similar manner to ReferentialExample 41.

¹H-NMR (CDCl₃) δ: 1.03 (9H, s), 1.20 (6H, s), 3.64-3.68 (5H, m),7.38-7.44 (6H, m), 7.63-7.65 (4H, m).

Referential Example 1583-{[tert-Butyl(diphenyl)silyl]oxy}-2,2-dimethylpropionic acid

Water (0.24 ml) was added to a suspension composed of potassiumtert-butoxide (5.32 g) and diethyl ether (100 ml) under ice cooling, andthe mixture was stirred for 5 minutes. The compound (2.22 g) obtained inReferential Example 157 was added thereto, and the resultant mixture wasstirred overnight at room temperature. Water was added to the reactionmixture, and the mixture was acidified with 1N hydrochloric acid andextracted 3 times with diethyl ether. After the resultant organic layerwas dried over anhydrous sodium sulfate, the solvent was distilled offunder reduced pressure, and the resultant residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:6) to obtain thetitle compound (735 mg).

¹H-NMR (CDCl₃) δ: 1.04 (9H, d, J=0.7 Hz), 1.22 (6H, s), 3.65 (2H, s),7.36-7.45 (6H, m), 7.64-7.66 (4H, m).

Referential Example 159 Methyl 3-methoxy-2,2-dimethylpropionate

A solution of methyl 3-hydroxy-2,2-dimethylpropionate (25.0 g) intetrahydrofuran (300 ml) was added dropwise to a suspension composed ofa 60% oil suspension of sodium hydride (8.32 g) and tetrahydrofuran (100ml) under ice cooling, and the mixture was stirred at 60° C. for 1 hour.Methyl iodide (53.7 g) was added to the reaction mixture, and theresultant mixture was stirred at room temperature for 2 hours. Water wascarefully added to conduct extraction twice with methylene chloride.After the resultant organic layer was washed with saturated aqueoussolution of sodium chloride and then dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure, and theresultant oil was distilled to obtain the title compound (12.8 g).

Boiling point: 140-142° C. (ordinary pressure).

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=1.0 Hz), 3.33 (3H, d, J=1.0 Hz), 3.38(2H, d, J=1.0 Hz), 3.69 (3H, d, J=1.0 Hz).

Referential Example 160 3-Methoxy-2,2-dimethylpropionic acid

The title compound was obtained from the compound obtained inReferential Example 159 in a similar manner to Referential Example 158.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=0.7 Hz), 3.38 (3H, d, J=0.7 Hz), 3.40(2H, d, J=0.7 Hz).

Referential Example 161 1-(Methoxycarbonyl)cyclopropanecarboxylic acid

Dimethyl 1,1-cyclopropanecarboxylate (25 g) was dissolved in methanol(250 ml), and the solution was cooled with ice. A 1N aqueous solution ofsodium hydroxide (158 ml) was then added dropwise, and the resultantmixture was warmed to room temperature and stirred overnight. Aftermethanol was distilled off, the residue was washed with chloroform, anda water layer was cooled with ice, adjusted to pH 2 with concentratedhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure to obtain the title compound (16.8 g).

¹H-NMR (CDCl₃) δ: 1.76-1.80 (2H, m), 1.82-1.88 (2H, m), 3.79 (3H, s),12.73 (1H, br).

Referential Example 162 Methyl 1-(hydroxymethyl)cyclopropanecarboxylate

The compound (9.0 g) obtained in Referential Example 161 andtriethylamine (9.7 ml) were dissolved in tetrahydrofuran (180 ml), andthe solution was cooled to −10° C., to which isobutyl chloroformate (9.1ml) was added dropwise, and the resultant mixture was stirred for 1hour. On the other hand, sodium borohydride (7.1 g) was dissolved intetrahydrofuran (100 ml)-water (25 ml) and cooled with ice. Whileremoving insoluble matter by filtration, the solution preparedpreviously was added dropwise, and the resultant mixture was stirred atthe same temperature for 1 hour. The reaction mixture was poured into acooled 10% aqueous solution of citric acid to conduct extraction withethyl acetate. After the extract was washed with saturated aqueoussolution of sodium chloride and then dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresultant residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:9-2:1) to obtain the title compound (4.25 g).

¹H-NMR (CDCl₃) δ: 0.87-0.93 (2H, m), 1.28-1.30 (2H, m), 3.63 (2H, s),3.70 (3H, s).

Referential Example 163 Methyl 1-(bromomethyl)cyclopropanecarboxylate

Triphenylphosphine (10 g) and carbon tetrabromide (16 g) were added to asolution of the compound (4.20 g) obtained in Referential Example 162 inmethylene chloride (168 ml) at room temperature under a nitrogenatmosphere. After 2 minutes, a saturated aqueous solution of sodiumhydrogencarbonate was added thereto. After the resultant organic layerwas washed with saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The resultant residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:19) to obtain thetitle compound (2.15 g).

¹H-NMR (CDCl₃) δ: 1.00-1.05 (2H, m), 1.52-1.59 (2H, m), 3.61 (2H, s),3.73 (3H, s).

Referential Example 164 tert-Butyl(4S)-4-[(E)-3-ethoxy-3-oxo-1-propenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A mixture solution composed of tert-Butyl(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (11.7 g),(carboethoxymethylene)triphenylphosphorane (20.7 g) and toluene (100 ml)was heated and stirred at 100° C. for 18 hours. The reaction mixture wasconcentrated, and the resultant residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=8:1) to obtain thetitle compound (17 g).

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=6.6 Hz), 1.43-1.56 (15H, m), 3.80 (1H,dd, J=9.0, 2.4 Hz), 4.09 (1H, dd, J=9.0, 6.6 Hz), 4.11-4.23 (2H, m),4.30-4.61 (1H, m), 5.83-6.02 (1H, m), 6.74-6.89 (1H, m).

Referential Example 165 tert-Butyl(4S)-4-[1-(benzylamino)-3-ethoxy-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A mixture solution composed of the compound (22.2 g) obtained inReferential Example 164, benzylamine (16 g) and ethanol (100 ml) washeated under reflux for 2 days. The reaction mixture was concentrated,and the resultant residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=8:1) to obtain the title compound (26g).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=6.6 Hz), 1.42-1.63 (15H, m), 2.24-2.33(0.5H, m), 2.40-2.50 (1H, m), 2.63-2.74 (0.5H, m), 3.41-3.52 (1H, m),3.67-3.80 (1H, m), 3.83 (2H, s), 3.89-4.00 (1H, m), 4.03-4.22 (4H, m),7.23-7.45 (5H, m).

Referential Example 166 tert-Butyl(4S)-4-(1-amino-3-ethoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

Palladium on carbon (10 g) was added to a solution of the compound (13.6g) obtained in Referential Example 165 in ethanol (200 ml), and themixture was stirred for 2 days under a hydrogen atmosphere. Insolublematter was removed through Celite pad, and the filtrate was concentratedunder reduced pressure to obtain the title compound (10.5 g).

¹H-NMR (DMSO-d₆) δ: 1.19 (1.5H, t, J=6.6 Hz), 1.20 (1.5H, t, J=6.6 Hz),1.32-1.50 (15H, m), 2.63-2.81 (2H, m), 3.22-3.34 (2H, m), 3.93 (1H, dd,J=10.0, 6.8 Hz), 4.08 (2H, q, J=6.6 Hz), 4.20-4.30 (1H, m).

Referential Example 167 tert-Butyl(4S)-4-(1-{[(benzyloxy)carbonyl]amino}-3-ethoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

The compound (3.0 g) obtained in Referential Example 166 was suspendedin a 9% aqueous solution (56 ml) of sodium hydrogencarbonate, and asolution of N-(benzyloxycarbonyloxy)succinimide (2.3 g) in dioxane (12ml) was added dropwise to the suspension under ice cooling. Theresultant mixture was stirred for 3 hours while the temperature of thesystem was gradually raised to room temperature. The reaction mixturewas diluted with ethyl acetate and washed with water, a 10% aqueoussolution of citric acid and saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel (chloroform) to obtainthe title compound (3.8 g).

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=6.6 Hz), 1.48 (9H, s), 1.56 (6H, s),2.40-2.51 (2H, m), 2.63-2.70 (2H, m), 3.92-4.04 (1H, m), 4.06-4.10 (2H,m), 4.14-4.22 (1H, m), 5.09 (2H, s), 7.30-7.43 (5H, m).

Referential Example 168 Ethyl(3S,4S)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-hydroxyvalerate(low-polar compound) and ethyl(3R,4S)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-hydroxyvalerate(high-polar compound)

Trifluoroacetic acid (100 ml) was added dropwise to a solution of thecompound (30 g) obtained in Referential Example 167 in methylenechloride (100 ml) under ice cooling, and the mixture was stirred for 3hours while the temperature of the system was gradually raised to roomtemperature. The reaction mixture was concentrated under reducedpressure, and the resultant residue was dissolved in methylene chloride(100 ml). Triethylamine (20 ml) and a solution of di-tert-butyldicarbonate (19 g) in methylene chloride (100 ml) were successivelyadded dropwise to this solution under ice cooling, and the mixture wasstirred for 4 hours while the temperature of the system was graduallyraised to room temperature. The reaction mixture was concentrated underreduced pressure, and the resultant residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:1) to obtain thetitle low-polar compound (7.6 g) and the title high-polar compound (10g).

Low-Polar Compound:

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=6.6 Hz), 1.42 (9H, s), 2.63 (2H, d,J=4.4 Hz), 3.30-3.41 (1H, m), 3.50 (1H, t, J=9.7 Hz), 3.65 (1H, t, J=9.7Hz), 3.75 (1H, d, J=11.7 Hz), 3.90-4.00 (1H, m), 4.03-4.23 (2H, m), 5.12(2H, s), 5.13-5.25 (1H, m), 5.79-6.02 (1H, m), 7.32-7.41 (5H, m).

High-Polar Compound:

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=6.6 Hz), 1.41 (9H, s), 2.50-2.70 (2H,m), 3.20-3.31 (1H, m), 3.43-3.51 (1H, m), 3.56-3.70 (1H, m), 3.74-3.78(1H, m), 4.00-4.19 (2H, m), 4.23-4.30 (1H, m), 4.78-4.89 (1H, m), 5.10(2H, s), 5.56-5.67 (1H, m), 7.31-7.40 (5H, m).

Referential Example 169(3R,4S)-4-[(Methylsulfonyl)oxy]tetrahydro-3-furanyl methanesulfonate

Triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) weresuccessively added dropwise to a solution of 1,4-anhydroerythritol (5.0g) in methylene chloride (50 ml) under ice cooling, and the mixture wasstirred for 10 minutes under ice cooling. The reaction mixture wasdiluted with methylene chloride and washed with 10% hydrochloric acid, asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride. After the resultant organic layerwas dried over anhydrous sodium sulfate, the solvent was distilled offunder reduced pressure to obtain the title compound (9.2 g).

¹H-NMR (CDCl₃) δ: 3.15 (6H, s), 3.99 (2H, dd, J=11.2, 2.5 Hz), 4.16 (2H,dd, J=11.2, 4.6 Hz), 5.10-5.20 (2H, m).

Referential Example 170 (3R,4S)-3,4-Diazidotetrahydrofuran

The compound (9.2 g) obtained in Referential Example 169 was dissolvedin N,N-dimethylformamide (50 ml), sodium azide (18 g) was added, and theresultant mixture was heated and stirred at 100° C. for 18 hours. Thereaction mixture was diluted with ethyl acetate and washed with waterand saturated aqueous solution of sodium chloride. After the resultantorganic layer was dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure to obtain the title compound (3.8g).

¹H-NMR (CDCl₃) δ: 3.83 (2H, dd, J=8.6, 2.0 Hz), 3.96-4.12 (4H, m).

Referential Example 171 (3R,4S)-Tetrahydro-3,4-furandiaminedihydrochloride

The compound (3.8 g) obtained in Referential Example 170 was dissolvedin ethanol (50 ml), 10 palladium on carbon (1.0 g) was added to thesolution, and the mixture was stirred for 18 hours under a hydrogenatmosphere. Insoluble matter was removed through Celite pad, and thefiltrate was concentrated under reduced pressure. A 1N ethanol solutionof hydrochloric acid was added to the resultant residue, giving thehydrochloride salt. The hydrochloride was recrystallized from a mixedsolvent of ethanol and diethyl ether to obtain the title compound (2.0g).

¹H-NMR (CDCl₃) δ: 3.90 (2H, dd, J=9.0, 3.7 Hz), 4.01-4.13 (4H, m), 8.84(6H, s).

Referential Example 172N-[(3R*,4S*)-4-Aminotetrahydro-3-furanyl]-5-chloroindole-2-carboxamide

5-Chloroindole-2-carboxylic acid (0.29 g), 1-hydroxybenzotriazolemonohydrate (0.2 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.6 g) were successively added to a solution of thecompound (0.5 g) obtained in Referential Example 171 inN,N-dimethylformamide (10 ml), and the mixture was heated and stirred at50° C. for a day. The reaction mixture was concentrated, and theresultant residue was diluted with a mixed solvent composed ofchloroform and methanol (9:1) and washed with a saturated aqueoussolution of sodium hydrogencarbonate and saturated aqueous solution ofsodium chloride. After the resultant organic layer was dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure, and the resultant residue was purified by columnchromatography on silica gel (chloroform:methanol=95:5) to obtain thetitle compound (0.2 g).

¹H-NMR (CDCl₃) δ: 1.80-1.92 (1H, m), 3.62 (1H, dd, J=9.3, 4.2 Hz),3.68-3.80 (2H, m), 4.06 (1H, dd, J=9.3, 5.6 Hz), 4.21 (1H, dd, J=9.3,6.8 Hz), 4.36-4.52 (2H, m), 6.87 (1H, s), 7.24 (1H, dd, J=8.8, 2.0 Hz),7.36 (1H, d, J=8.8 Hz), 7.44-7.56 (1H, m), 7.62 (1H, d, J=2.0 Hz), 9.41(1H, s).

Referential Example 173 tert-Buthyl(4R)-4-[(E)-3-ethoxy-3-oxo-1-propenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

The title compound was obtained from tert-Butyl(4S)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate in a similarmanner to Referential Example 164.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=6.6 Hz), 1.40-1.60 (15H, m), 3.80 (1H,dd, J=9.0, 2.4 Hz), 4.09 (1H, dd, J=9.0, 6.6 Hz), 4.11-4.21 (2H, m),4.32-4.64 (1H, m), 5.78-6.01 (1H, m), 6.67-6.89 (1H, m).

Referential Example 174 tert-Butyl(4R)-4-[1-(benzylamino)-3-ethoxy-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

The title compound was obtained from the compound obtained inReferential Example 173 in a similar manner to Referential Example 165.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=6.6 Hz), 1.40-1.61 (15H, m), 2.21-2.32(0.5H, m), 2.40-2.51 (1H, m), 2.61-2.72 (0.5H, m), 3.43-3.50 (1H, m),3.67-3.80 (1H, m), 3.83 (2H, s), 3.90-4.03 (1H, m), 4.04-4.22 (4H, m),7.20-7.40 (5H, m).

Referential Example 175 tert-Butyl(4R)-4-(1-{[(5-chloroindol-2-yl)carbonyl]amino}-3-ethoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

The title compound was obtained by reducing the compound obtained inReferential Example 174 in a similar manner to Referential Example 166to remove a benzyl group and then condensing it with5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 172.

¹H-NMR (CDCl₃) δ: 1.23 (1.5H, t, J=6.6 Hz), 1.25 (1.5H, t, J=6.6 Hz),1.50 (4.5H, s), 1.54 (4.5H, s), 1.62 (6H, s), 2.50-2.70 (1.5H, m), 2.86(0.5H, dd, J=16.4, 5.5 Hz), 3.80-3.90 (0.5H, m), 4.00-4.31 (5H, m),4.41-4.67 (0.5H, m), 6.85 (0.5H, s), 6.87 (0.5H, s), 7.10-7.20 (1H, m),7.34 (0.5H, d, J=8.8 Hz), 7.38 (0.5H, d, J=8.8 Hz), 7.57 (0.5H, s), 7.63(0.5H, s), 7.88 (0.5H, d, J=7.6 Hz), 8.54 (0.5H, d, J=7.6 Hz), 9.40(0.5H, s), 9.54 (0.5H, s).

Referential Example 176 tert-Butyl(3R,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyran-3-ylcarbamate(low-polar compound) and tert-butyl and(3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]-amino}-6-oxotetrahydro-2H-pyran-3-ylcarbamate(high-polar compound)

A 1N aqueous solution (4.0 ml) of sodium hydroxide was added to asolution of the compound (1.0 g) obtained in Referential Example 175 inethanol (20 ml), and the mixture was stirred for 4 hours. Citric acidwas added to the reaction mixture to adjust the pH of the reactionmixture to 4.0. The reaction mixture was extracted with ethyl acetate,and the resultant organic layer was washed with saturated aqueoussolution of sodium chloride and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresultant residue was dissolved in methanol (50 ml), and toluenesulfonicacid monohydrate (0.1 g) was added to the solution to stir the resultantmixture for 18 hours. The reaction mixture was diluted with ethylacetate and washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride. Theresultant organic layer was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by column chromatography on silica gel(chloroform:methanol=99:1) to obtain the title low-polar compound (0.3g) and the title high-polar compound (0.3 g).

Low-Polar Compound:

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.70 (1H, dd, J=16.5, 4.9 Hz), 2.85 (1H,dd, J=16.5, 4.6 Hz), 3.50-3.61 (1H, m), 3.71-3.81 (2H, m), 4.30-4.40(1H, m), 5.30 (1H, d, J=9.5 Hz), 6.89 (1H, s), 7.23 (1H, dd, J=8.8, 2.0Hz), 7.38 (1H, d, J=8.8 Hz), 7.62 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=9.5Hz), 9.30 (1H, s).

High-Polar Compound:

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 2.75 (1H, dd, J=16.5, 4.9 Hz), 2.82 (1H,dd, J=16.5, 4.6 Hz), 3.41-3.52 (2H, m), 3.71-3.82 (1H, m), 3.85-3.94(1H, m), 5.03 (1H, d, J=9.3 Hz), 6.99 (1H, s), 7.22-7.31 (1H, m), 7.34(1H, d, J=8.8 Hz), 7.61 (1H, d, J=2.0 Hz), 7.83 (1H, d, J=9.3 Hz), 9.28(1H, s).

Referential Example 177 tert-Butyl1,1,3-trioxohexahydro-1-thiopyran-4-ylcarbamate

A solution of N-tert-butoxycarbonyl-L-methionine sulfone methyl ester(60.2 g) in tetrahydrofuran (900 ml) was cooled to −78° C., to which 0.5M potassium bis(trimethylsilyl)amide (toluene solution, 900 ml) wasadded dropwise, and the mixture was stirred for 2 hours at −78° C. andfor 4.5 hours at room temperature. A 1 M aqueous solution of ammoniumchloride was added, and the mixture was stirred. The reaction mixturewas subjected to liquid separation, and the resultant organic layer wasthen washed with water and saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and solids formed were collected byfiltration to obtain the title compound (12.4 g). The water layerseparated previously was extracted twice with ethyl acetate, and theresultant organic layers were combined, washed with water and saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The water layers used in the washing were further combined, andextracted again with ethyl acetate, and the extract was washed withsaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. The ethyl acetate extracts were combined, dried andthen concentrated under reduced pressure to obtain the title compound(27.7 g) (total amount of the title compound: 40.1 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.85-1.96 (1H, m), 2.76-2.78 (1H, m),3.34-3.46 (2H, m), 4.05 (1H, dd, J=13.5, 3.7 Hz), 4.14 (1H, d, J=13.5Hz), 4.38-4.44 (1H, m), 5.46 (1H, br).

MS (ESI) m/z: 262 (M−H)⁻.

Referential Example 178 tert-Butyl(3R*,4R*)-3-hydroxy-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate

Sodium borohydride (2.17 g) was added to a suspension of the compound(10.1 g) obtained in Referential Example 177 in methanol (200 ml), andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure. After ethyl acetate anda saturated aqueous solution of sodium hydrogencarbonate were added tothe residue to conduct liquid separation, the resultant water layer wasextracted twice with ethyl acetate. The resultant organic layers werecombined, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure to obtain the title compound (9.96 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.21-2.36 (2H, m), 3.03-3.17 (2H, m),3.26-3.28 (2H, m), 3.77-3.80 (2H, m), 4.26-4.28 (1H, m), 5.05-5.07 (1H,m).

MS (ESI) m/z: 264 (M−H)⁻.

Referential Example 179 tert-Butyl(3R*,4R*)-3-amino-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate(low-polar compound) and tert-Butyl(3R*,4S*)-3-amino-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate(high-polar compound)

Diethyl azodicarboxylate (6.96 g) was added to a solution of thecompound (9.66 g) obtained in Referential Example 178 andtriphenylphosphine (10.5 g) in tetrahydrofuran (150 ml), and the mixturewas stirred at room temperature for 4.5 hours. After the reactionmixture was concentrated under reduced pressure, diethyl ether was addedto the residue, and solids formed were collected by filtration. Thethus-collected solids were purified by column chromatography on silicagel (hexane:ethyl acetate=7:3) to obtain a mixture (7.25 g) containingtert-butyl 1,1-dioxo-1,2,3,4-tetrahydropyran-4-ylcarbamate as acolorless solid. The mother liquor was concentrated under reducedpressure, and the resultant residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=7:3) to obtain amixture (9.18 g) containing tert-butyl1,1-dioxo-1,2,3,4-tetrahydropyran-4-ylcarbamate as a colorless solid(total amount: 16.4 g). The thus-obtained mixtures were dissolved indioxane (60 ml), and 28% aqueous ammonia (60 ml) was added. Theresultant mixture was stirred at 60° C. for 4.5 hours in a sealed tube.After allowing to cool, the reaction mixture was concentrated underreduced pressure. After dioxane was distilled off, the residue wasextracted 5 times with methylene chloride. The resultant organic layerswere combined and concentrated under reduced pressure. The resultantresidue was purified by column chromatography on silica gel (methylenechloride:methanol=96:4) to obtain the title low-polar compound (2.31 g)and the title high-polar compound (4.31 g).

Low-Polar Compound:

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.14-2.28 (2H, m), 3.01-3.08 (3H, m),3.23 (1H, dd, J=13.8, 3.9 Hz), 3.47-3.49 (1H, m), 3.71-3.76 (1H, m),5.32 (1H, d, J=7.3 Hz).

MS (ESI) m/z: 265 (M+H⁺).

High-Polar Compound:

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.94-2.01 (1H, m), 2.37-2.44 (1H, m),2.91 (1H, dd, J=11.2, 14.1 Hz), 3.04-3.07 (2H, m), 3.12-3.19 (1H, m),3.26-3.30 (1H, m), 3.39-3.42 (1H, m), 4.62 (1H, br).

MS (ESI) m/z: 265 (M+H⁺).

Referential Example 180 (2S,3S)-2,3-Bis(methoxymethoxy)-1,4-butanediol

Chloromethyl methyl ether (4.8 ml) was added dropwise to a mixturesolution composed of diethyl L-tartrate (8.6 g), diisopropylethylamine(40 ml) and methylene chloride (40 ml) under ice cooling, and themixture was stirred for 18 hours while the temperature of the system wasgradually raised to room temperature. The reaction mixture wasconcentrated, and the resultant residue was diluted with ethyl acetateand washed with 10% hydrochloric acid, a saturated aqueous solution ofsodium hydrogencarbonate and saturated aqueous solution of sodiumchloride. After the resultant organic layer was dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure,and the resultant residue was dissolved in tetrahydrofuran. The solutionwas added dropwise to a tetrahydrofuran suspension of lithium aluminumhydride (2.2 g) under ice cooling, and the mixture was stirred for 2hours under ice cooling. After a 10% aqueous solution of sodiumhydrogensulfate was carefully added under ice cooling, and the mixturewas stirred for 1 hour, the reaction mixture was diluted with saturatedaqueous solution of sodium chloride and extracted with ethyl acetate.After the resultant organic layer was dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure to obtainthe title compound (3.0 g).

¹H-NMR (CDCl₃) δ: 1.55-1.64 (2H, m), 3.44 (6H, s), 3.70-3.81 (6H, m),4.70 (2H, d, J=6.9 Hz), 4.76 (2H, d, J=6.9 Hz).

Referential Example 181 (3S,4S)-3,4-Bis(methoxymethoxy)tetrahydrofuran

Diethyl azodicarboxylate (2.46 ml) was added dropwise to a mixturesolution composed of the compound (3.0 g) obtained in ReferentialExample 180, triphenylphosphine (4.5 g), tetrahydrofuran (10 ml) andtoluene (40 ml), and the mixture was stirred at room temperature for 4days. The reaction mixture was concentrated under reduced pressure, amixed solvent (160 ml) of hexane and diethyl ether (1:1) was added tothe resultant residue, and the mixture was stirred for 3 hours.Insoluble matter deposited was then collected by filtration. Thefiltrate was concentrated, and the resultant residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=4:1) to obtainthe title compound (1.95 g).

¹H-NMR (CDCl₃) δ: 3.38 (6H, s), 3.80 (2H, dd, J=9.2, 1.7 Hz), 4.00 (2H,dd, J=9.2, 4.4 Hz), 4.23 (2H, dd, J=4.4, 1.7 Hz), 4.67 (2H, d, J=6.9Hz), 4.71 (2H, d, J=6.9 Hz).

Referential Example 182 (3S,4S)-Tetrahydro-3,4-furandiol

Concentrated hydrochloric acid (2.1 ml) was added to a solution of thecompound (1.95 g) obtained in Referential Example 181 in methanol (6.0ml), and the mixture was stirred for 18 hours. After the reactionmixture was concentrated, and the resultant residue was diluted withchloroform and dried over potassium carbonate, the solvent was distilledoff under reduced pressure to obtain the title compound (0.52 g).

¹H-NMR (CDCl₃) δ: 1.77 (2H, d, J=4.7 Hz), 3.73 (2H, d, J=10.2 Hz), 4.08(2H, dd, J=10.2, 3.7 Hz), 4.18-4.34 (2H, m).

Referential Example 183 (3S,4S)-Tetrahydro-3,4-furandiamine

The title compound was obtained from the compound obtained inReferential Example 182 in a similar manner to the processes describedin Referential Examples 169 to 171.

¹H-NMR (CDCl₃) δ: 1.35-1.46 (4H, m), 3.19 (2H, dd, J=5.6, 4.1 Hz), 3.50(2H, dd, J=9.0, 4.1 Hz), 4.09 (2H, dd, J=9.0, 5.6 Hz).

Referential Example 184 (2R,3R)-2,3-Bis(methoxymethoxy)-1,4-butanediol

The title compound was obtained from diethyl D-tartrate in a similarmanner to Referential Example 180.

¹H-NMR: The same as that of the enantiomer in Referential Example 180.

Referential Example 185 (3R,4R)-3,4-Bis(methoxymethoxy)tetrahydrofuran

The title compound was obtained from the compound obtained inReferential Example 184 in a similar manner to Referential Example 181.

¹H-NMR: The same as that of the enantiomer in Referential Example 181.

Referential Example 186 (3R,4R)-Tetrahydro-3,4-furandiol

The title compound was obtained from the compound obtained inReferential Example 185 in a similar manner to Referential Example 182.

¹H-NMR: The same as that of the enantiomer in Referential Example 182.

Referential Example 187 (3R,4R)-Tetrahydro-3,4-furandiamine

The title compound was obtained from the compound obtained inReferential Example 186 in a similar manner to Referential Example 183.

¹H-NMR (CDCl₃) δ: The same as that of the enantiomer in ReferentialExample 183.

Referential Example 188(3R,4R)-1-Benzyl-3,4-dihydroxy-2,5-pyrrolidinedione

L-Tartaric acid (30 g) and benzylamine (22 ml) were added to xylene (150ml), and the mixture was heated under reflux at 150° C. for 3 hoursusing a Dean-Stark trap. After the reaction mixture was allowed to coolovernight, crystals were collected by filtration and washed withacetone. The resultant crude product was recrystallized from ethanol toobtain the title compound (23.2 g).

¹H-NMR (DMSO-d₆) δ: 4.36-4.40 (2H, m), 4.55 (each 1H, AB type d, J=15Hz), 6.26-6.30 (2H, m), 7.25-7.35 (5H, m).

Referential Example 189 (3S,4S)-1-Benzyl-3,4-pyrrolidinediol

The compound (11 g) obtained in Referential Example 188 was dissolved intetrahydrofuran (110 ml), and lithium aluminum hydride (5.69 g) wasadded portionwise to the solution under ice cooling. The mixture washeated to room temperature for 1 hour and heated under reflux and foradditional a night. After allowing the reaction mixture to cool, water(5.7 ml), a 15% aqueous solution (5.7 ml) of sodium hydroxide and water(17.1 ml) were added under ice cooling in that order, and the mixturewas heated to room temperature and stirred for 1 hour. After depositswere filtered through Celite, and the mother liquor was concentratedunder reduced pressure, the resultant residue was recrystallized fromethyl acetate to obtain title compound (6.35 g).

¹H-NMR (CDCl₃) δ: 2.40-2.44 (2H, m), 2.88-2.92 (2H, m), 3.58 (each 1H,AB type d, J=7.8 Hz), 4.04 (2H, t, J=4.2 Hz), 7.25-7.34 (5H, m).

Referential Example 190(3S,4S)-1-Benzyl-4-[(methylsulfonyl)oxy]pyrrolidinyl methanesulfonate

The title compound was obtained from the compound obtained inReferential Example 189 in a similar manner to Referential Example 169.

¹H-NMR (CDCl₃) δ: 2.76 (2H, dd, J=11, 4.6 Hz), 3.08 (6H, s), 3.64 (2H,d, J=2.5 Hz), 3.68-3.75 (2H, m), 5.12-5.15 (2H, m), 7.27-7.35 (5H, m).

Referential Example 191 tert-Butyl(3S,4S)-3,4-bis[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate

The compound (1.57 g) obtained in Referential Example 190 was dissolvedin 1,2-dichloroethane (16 ml), 1-chloroethyl chloroformate (0.73 ml) wasadded at room temperature, and the resultant mixture was heated underreflux for 4 hours. After the solvent was distilled off under reducedpressure, methanol (16 ml) was added to the resultant residue, and theresultant mixture was heated under reflux for 1 hour, allowed to cooland concentrated. Crystals obtained by recrystallization from ethylacetate were collected by filtration to obtain(3S,4S)-3,4-bis-[(methylsulfonyl)oxy]pyrrolidine hydrochloride (1.30 g)as colorless crystals. Di-tert-butyl dicarbonate (1.15 ml) was added toa solution of the hydrochloride thus obtained and triethylamine (1.40ml) in methylene chloride (26 ml), and the mixture was stirred overnightat room temperature. After the reaction mixture was concentrated, theresidue was diluted with ethyl acetate, washed with water and saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresultant residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:9-1:1) to obtain the title compound (1.40 g).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.12 (6H, s), 3.70-3.73 (2H, m), 3.79(1H, d, J=4.5 Hz), 3.82 (1H, d, J=4.5 Hz), 5.19 (2H, br).

Referential Example 192 tert-Butyl(3R,4R)-3,4-diazido-1-pyrrolidinecarboxylate

The title compound was obtained from the compound obtained inReferential Example 191 in a similar manner to Referential Example 170.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.37-3.46 (2H, m), 3.64-3.71 (2H, m),3.96 (2H, t, J=3.2 Hz).

Referential Example 193 tert-Butyl(3R,4R)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}pyrrolidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 192 in a similar manner to Referential Examples 171and 172.

¹H-NMR (DMSO-d₆) δ: 1.39 (9H, s), 2.95-3.00 (1H, m), 3.09-3.13 (1H, m),3.52 (1H, dd, J=10, 6.5 Hz), 3.68 (1H, dd, J=10, 7.8 Hz), 4.04-4.09 (2H,m), 7.16 (1H, s), 7.18 (1H, s), 7.42 (1H, d, J=8.5 Hz), 7.69 (1H, d,J=1.5 Hz), 8.50 (1H, d, J=6.5 Hz), 11.77 (1H, br).

Referential Example 194 tert-Butyl(3S)-5-oxotetrahydro-3-furanylcarbamate

di-tert-Butyl dicarbonate (4.1 g) and 10% palladium on carbon (0.4 g)were added to a solution of benzyl(3S)-(−)-tetrahydro-5-oxo-3-furanylcarbamate (3.3 g) in tetrahydrofuran(20 ml), and the mixture was stirred for a day in a hydrogen atmosphere.After insoluble matter was filtered through Celite pad, the filtrate wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=4:1) to obtainthe title compound (1.5 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.45 (1H, dd, J=17.8, 2.7 Hz), 2.86 (1H,dd, J=17.8, 7.3 Hz), 4.12-4.23 (1H, m), 4.54-4.62 (2H, m), 4.85-4.95(1H, m).

Referential Example 195 tert-Butyl(3S,4S)-4-azido-5-oxotetrahydro-3-furanylcarbamate

1 M Lithium bis(trimethylsilyl)amide (tetrahydrofuran solution, 8.65 ml)was added dropwise to a solution of the compound (0.87 g) obtained inReferential Example 194 in tetrahydrofuran (20 ml) at −78° C., and themixture was stirred for 30 minutes. After a solution ofp-toluenesulfonylazide (1.02 g) in tetrahydrofuran (10 ml) was thenadded, and the mixture was stirred for 5 minutes, trimethylchlorosilane(1.7 ml) was added, and the mixture was stirred for 2 hours while thetemperature of the system was gradually raised to room temperature. Thereaction mixture was diluted with diethyl ether, washed with 10%hydrochloric acid, a 5% saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride, andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure. The resultant residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=4:1) to obtain thetitle compound (0.62 g).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 4.09 (1H, dt, J=15.3, 7.6 Hz), 4.12-4.23(1H, m), 4.37-4.50 (1H, m), 4.54 (1H, dd, J=9.0, 7.6 Hz), 4.81-4.90 (1H,m).

Referential Example 196 tert-Butyl(3S,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-5-oxotetrahydro-3-furanylcarbamate

The title compound was obtained from the compound obtained inReferential Example 195 in a similar manner to Referential Examples 90and 91.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 4.01-4.13 (1H, m), 4.20-4.36 (1H, m),4.78-4.93 (2H, m), 6.15 (1H, s), 6.93 (1H, s), 7.03-7.11 (1H, m),7.20-7.28 (1H, m), 7.30 (1H, d, J=8.8 Hz), 7.61 (1H, s), 9.27 (1H, s).

Referential Example 197 tert-Butyl(3S,4S)-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-5-oxotetrahydro-3-furanylcarbamate

The title compound was obtained by getting tert-butyl(3S,4S)-4-amino-5-oxotetrahydro-3-furanylcarboxylate from the compoundobtained in Referential Example 195 in a similar manner to ReferentialExample 90 and then reacting with the compound obtained in ReferentialExample 10 in accordance with the reaction conditions of ReferentialExample 91.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.52 (3H, s), 2.83 (2H, t, J=5.9 Hz),2.79-3.02 (2H, m), 3.74 (2H, s), 4.03-4.12 (1H, m), 4.21-4.36 (1H, m),4.80-4.95 (2H, m), 6.14-6.24 (1H, m), 7.76-7.85 (1H, m).

Referential Example 198 Ethyl2-[((3S)-3-[(tert-butoxycarbonyl)amino]-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-hydroxybutanoyl)amino]acetate

The compound (0.4 g) obtained in Referential Example 196, glycine ethylester hydrochloride (1.0 g) and triethylamine (1.0 ml) were added toethanol (20 ml), and the mixture was heated and stirred at 60° C. for 18hours. The reaction mixture was diluted with chloroform and washed witha 10% aqueous solution of citric acid and saturated aqueous solution ofsodium chloride. The resultant organic layer was dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by column chromatography onsilica gel (chloroform:methanol=98:2) to obtain title compound (0.31 g).

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.0 Hz), 1.34 (6H, s), 1.36 (3H, s),3.51-3.63 (0.6H, m), 3.72-3.80 (2H, m), 4.06 (2H, q, J=7.0 Hz),4.11-4.23 (1.4H, m), 4.67-4.82 (1H, m), 4.85-4.91 (1H, m), 6.48 (0.4H,d, J=9.5 Hz), 6.80 (0.6H, d, J=9.5 Hz), 7.10-7.22 (2H, m), 7.42 (1H, d,J=8.8 Hz), 7.72 (0.4H, d, J=2.0 Hz), 7.73 (0.6H, d, J=2.0 Hz), 8.23-8.31(0.6H, m), 8.34-8.41 (0.4H, m), 8.43-8.50 (1H, m), 11.83 (1H, s).

Referential Example 199 Ethyl2-((4R)-4-amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}-2-oxopyrrolidin-1-yl)acetatehydrochloride

The title compound was obtained by converting the compound obtained inReferential Example 198 into a pyrrolidone derivative using the reactionconditions described in Referential Example 181 and then removing atert-butoxycarbonyl group in a similar manner to Referential Example 69.

¹H-NMR (DMSO-d₆) δ: 1.17 (2H, t, J=7.0 Hz), 1.23 (1H, t, J=7.0 Hz),3.31-3.40 (0.6H, m), 3.57 (0.4H, d, J=11.2 Hz), 3.90-4.23 (4H, m), 4.42(0.6H, dd, J=12.0, 6.1 Hz), 4.50-4.60 (0.4H, m), 4.62 (0.6H, dd, J=12.0,3.9 Hz), 5.12-5.23 (0.4H, m), 7.17 (0.4H, s), 7.20 (0.4H, dd, J=8.8, 2.0Hz), 7.28 (0.6H, dd, J=8.8, 2.0 Hz), 7.30 (0.6H, s), 7.44 (0.4H, d,J=8.8 Hz), 7.50 (0.6H, d, J=8.8 Hz), 7.75 (1H, d, J=2.0 Hz), 8.20-8.33(1H, m), 8.71-8.94 (3.6H, m), 9.22-9.35 (0.4H, m), 11.97 (0.4H, s),12.44 (0.6H, s).

Referential Example 200 tert-Butyl(3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-5-oxopyrrolidin-3-ylcarbamate

The title compound was obtained by treating a compound obtained byreaction of the compound obtained in Referential Example 196 withmethylamine (40% methanol solution) in a similar manner to ReferentialExample 198 under the same conditions as those in Referential Example181.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.90 (3H, s), 4.26 (1H, br.s), 4.36 (2H,m), 4.51-4.52 (1H, m), 5.35 (1H, br.s), 6.95-6.99 (2H, m), 7.22-7.32(3H, m), 7.63 (1H, s), 8.95 (1H, br.s).

Referential Example 201N-[(3S,4R)-4-Amino-1-methyl-2-oxopyrrolidin-3-yl]-5-chloroindole-2-carboxamide

The title compound was obtained by treating the compound obtained inReferential Example 200 in a similar manner to Referential Example 69.

¹H-NMR (CDCl₃) δ: 2.95 (3H, d, J=5.1 Hz), 3.91-3.93 (1H, m), 4.19 (1H,d, J=3.7 Hz), 4.36 (1H, dd, J=11, 1.7 Hz), 4.48 (1H, dd, J=11, 2.0 Hz),6.90-6.97 (2H, m), 7.21-7.33 (2H, m), 7.62 (1H, d, J=2.0 Hz), 8.90 (1H,s).

Referential Example 202 tert-Butyl 3,6-dihydro-1(2H)-pyridinecarboxylate

tert-Butyl dicarbonate (6.55 g) was added to a mixture of1,2,3,6-tetrahydropyridine (2.50 g) and a 10% aqueous solution (3.0 ml)of sodium carbonate, and the mixture was stirred at room temperature for20 hours. Water was added to the reaction mixture to conduct extractionwith ethyl acetate. The resultant organic layer was washed with 0.5Nhydrochloric acid, water, a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride inthat order and dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure to obtain the title compound (5.08g).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.12 (2H, br.s), 3.48 (2H, t, J=5.6 Hz),3.88 (2H, br.s), 5.60 (1H, br.s), 5.78-5.90 (1H, m).

Referential Example 203 tert-Butyl(3R*,4S*)-3,4-dihydroxy-1-piperidinecarboxylate

The compound (18.45 g) obtained in Referential Example 202 was dissolvedin acetonitrile (200 ml), and water (38 ml), a 0.039 M aqueous solution(82 ml) of osmium tetroxide and N-methylmorpholine N-oxide (23.13 g)were added. The mixture was stirred at room temperature for 17 hours. Anexcessive oxidizing agent was treated with a saturated aqueous solutionof sodium sulfite to conduct extraction with ethyl acetate. Theresultant organic layer was washed with water, 0.5N hydrochloric acid,water, a saturated aqueous solution of sodium hydrogencarbonate andsaturated aqueous solution of sodium chloride in that order, dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The resultant residue was purified by column chromatography on silicagel (hexane:ethyl acetate=1:3) to obtain the title compound (15.0 g).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.60-1.73 (1H, m), 1.77-1.90 (1H, m),2.68 (1H, br.s), 2.80-3.20 (1H, br), 3.22-3.32 (1H, m), 3.42 (1H, dd,J=14.3, 3.4 Hz), 3.50-3.62 (2H, m), 3.77 (1H, brs), 3.81-3.92 (1H, m).

Referential Example 204 tert-Butyl(3R*,4S*)-3,4-bis[(methylsulfonyl)oxy]-1-piperidinecarboxylate

The title compound was obtained from the compound obtained inReferential Example 203 in a similar manner to Referential Example 169.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.85-1.97 (1H, m), 2.08-2.20 (1H, m),3.00-4.20 (4H, m), 3.12 (6H, s), 4.85 (1H, br.s), 4.94 (1H, br.s).

Referential Example 205 tert-Butyl(3R*,4S*)-3,4-diazido-1-piperidinecarboxylate

The title compound was obtained from the compound obtained inReferential Example 204 in a similar manner to Referential Example 170.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.70-1.80 (1H, m), 1.90-2.00 (1H, m),3.05-4.00 (6H, m).

Referential Example 206 tert-Butyl(3R*,4S*)-3,4-diamino-1-piperidinecarboxylate

The title compound was obtained from the compound obtained inReferential Example 205 in a similar manner to Referential Example 171.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.48-1.60 (2H, m), 1.80-2.10 (4H, br),2.85-2.91 (2H, m), 2.97 (1H, br.s), 3.09 (1H, dd, J=13.6, 2.7 Hz), 3.74(1H, dd, J=13.6, 4.2 Hz), 3.81 (1H, s).

Referential Example 207 tert-Butyl(3R*,4S*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-piperidinecarboxylate

The compound (3.23 g) obtained in Referential Example 206 was dissolvedin N,N-dimethylformamide (100 ml), and triethylamine (2.08 ml) and thecompound (3.80 g) obtained in Referential Example 52 were added to thesolution. The mixture was stirred at room temperature for 3 days. Thereaction mixture was concentrated under reduced pressure, and water wasadded to the residue to conduct extraction with methylene chloride. Theresultant organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The resultant residue was purified by columnchromatography on silica gel (methylene chloride:methanol=20:1-10:1) toobtain the title compound (2.70 g).

¹H-NMR (DMSO-d₆) δ: 1.40-1.58 (3H, m), 1.41 (9H, s), 1.75-1.90 (1H, m),2.95 (1H, br.s), 2.98-3.05 (1H, m), 3.19-3.28 (1H, m), 3.74 (1H, dd,J=19.5, 15.4 Hz), 3.79 (1H, br.s), 4.04-4.12 (1H, m), 7.17 (1H, dd,J=8.7, 1.9 Hz), 7.21 (1H, s), 7.42 (1H, d, J=8.7 Hz), 7.68 (1H, d, J=1.9Hz), 8.00 (1H, br.d, J=7.6 Hz), 11.80 (1H, s).

Referential Example 208 tert-Butyl(3R*,4S*)-3-amino-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-1-piperidinecarboxylate

The compound (3.23 g) obtained in Referential Example 206 was dissolvedin N,N-dimethylformamide (100 ml), and triethylamine (2.08 ml) wasadded. The compound (3.83 g) obtained in Referential Example 149 wasthen added, and the mixture was stirred at room temperature for 3 days.The reaction mixture was concentrated under reduced pressure, and waterwas added to the residue to conduct extraction with methylene chloride.The resultant organic layer was washed with a saturated aqueous solutionof sodium hydrogencarbonate and saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby column chromatography on silica gel (methylenechloride:methanol=10:1-5:1) to obtain the title compound (2.27 g).

¹H-NMR (CDCl₃) δ: 1.30-1.62 (3H, m), 1.47 (9H, s), 1.78-1.88 (1H, m),2.51 (3H, s), 2.81 (2H, t, J=5.9 Hz), 2.85-2.98 (3H, m), 3.00-3.15 (2H,m), 3.71 (2H, s), 3.80-4.15 (3H, m), 7.79 (1H, br.s).

Referential Example 209 tert-Butyl(3R*,4S*)-3-amino-4-{[(5-fluoroindol-2-yl)carbonyl]amino}-1-piperidinecarboxylate

The title compound was obtained from the compound obtained inReferential Example 206 and 5-fluoroindole-2-carboxylic acid in asimilar manner to Referential Example 172.

¹H-NMR (CDCl₃) δ: 1.40-1.70 (3H, m), 1.48 (9H, s), 2.79-2.92 (1H, m),2.99-3.14 (1H, m), 4.00-4.23 (3H, m), 6.85 (1H, s), 7.04 (1H, td, J=9.0,2.4 Hz), 7.07-7.20 (1H, br), 7.27 (1H, dd, J=9.0, 2.4 Hz), 7.35 (1H, d,J=9.0, 4.4 Hz), 9.25-9.50 (1H, br).

MS (ESI) m/z: 377 (M+H)⁺.

Referential Example 210 Ethyl(3S,4R)-5-azido-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]valerate

Triethylamine (4.80 ml) and methanesulfonyl chloride (1.55 ml) weresuccessively added dropwise to a solution of the (3S,4S)-compoundobtained in Referential Example 168 (low-polar compound) (7.1 g) inmethylene chloride (100 ml) under ice cooling, and the mixture wasstirred for 30 minutes under ice cooling. The reaction mixture wasdiluted with chloroform and washed with a 10% aqueous solution of citricacid, a saturated aqueous solution of sodium hydrogencarbonate andsaturated aqueous solution of sodium chloride. After the resultantorganic layer was dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure to obtain a methanesulfonylderivative (9.20 g). A mixture solution composed of the thus-obtainedmethanesulfonyl derivative, sodium azide (5.64 g) andN,N-dimethylformamide (100 ml) was stirred at 80° C. for 20 hours. Thereaction mixture was diluted with ethyl acetate and washed with waterand saturated aqueous solution of sodium chloride. After the resultantorganic layer was dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel (chloroform) to obtainthe title compound (5.42 g).

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.1 Hz), 1.43 (9H, s), 2.56-2.68 (2H,m), 3.48-3.60 (2H, m), 3.88-3.97 (1H, m), 4.04-4.20 (3H, m), 4.88-4.97(1H, br), 5.10 (2H, s), 5.60-5.75 (1H, br), 7.30-7.40 (5H, m).

MS (ESI) m/z: 436 (M+H)⁺.

Referential Example 211 Benzyl(4S,5R)-5-[(tert-butoxycarbonyl)amino]-2-oxopiperidin-4-ylcarbamate

A Lindlar catalyst (2.71 g) was added to a solution of the compound(5.42 g) obtained in Referential Example 210 in a mixed solvent ofethanol (150 ml) and tetrahydrofuran (10.0 ml), and the mixture wasstirred for 3 hours under a hydrogen atmosphere and then for 14 hoursunder nitrogen conditions. After insoluble matter was removed throughCelite pad, and the filtrate was concentrated under reduced pressure,the resultant residue was dissolved in tetrahydrofuran (30 ml), andtriethylamine (3.0 ml) was added thereto. The mixture was stirred atroom temperature for 1.5 hours. The reaction mixture was diluted withethyl acetate and washed with a 10% aqueous solution of citric acid, asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride. After the resultant organic layerwas dried over anhydrous sodium sulfate, the solvent was distilled offunder reduced pressure, and the resultant residue was purified by columnchromatography on silica gel (chloroform:methanol=25:1) to obtain thetitle compound (2.50 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.30-2.50 (1H, br), 2.65-2.90 (1H, br),3.15-3.30 (1H, br), 3.35-3.65 (1H, br), 4.00-4.25 (2H, br), 5.11 (2H,s), 5.55-5.60 (1H, br), 5.65-5.90 (1H, br), 6.25-6.55 (1H, br),7.28-7.40 (5H, m).

MS (ESI) m/z: 364 (M+H)⁺.

Referential Example 212 Benzyl(3R,4S)-3-[(tert-butoxycarbonyl)amino]piperidin-4-ylcarbamate

1 M Borane.tetrahydrofuran complex (tetrahydrofuran solution, 34.0 ml)was added dropwise to a tetrahydrofuran solution (70 μl) of the compound(2.49 g) obtained in Referential Example 211 under ice cooling, and themixture was stirred for 20 hours while the temperature of the system wasgradually raised to room temperature. Methanol (100 ml) was added to thereaction mixture, and the solvent was distilled off under reducedpressure. Ethanol (45 ml), water (5 ml) and triethylamine (10 ml) wereadded to the residue, and the mixture was heated under reflux for 24hours. The reaction mixture was concentrated, and the resultant residuewas purified by column chromatography on silica gel(chloroform:methanol:water=7:3:1, lower layer) to obtain the titlecompound (1.61 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.65-1.72 (2H, m), 2.67 (1H, t, J=12.0Hz), 2.82 (12H, d, J=12.0 Hz), 2.90-3.10 (1H, br), 3.60-3.80 (2H, m),3.90-4.00 (1H, m), 5.00-5.20 (2H, m), 5.40-5.60 (2H, br), 7.25-7.74 (5H,m).

MS (FAB) m/z: 350 (M+H)⁺.

Referential Example 213 tert-Buthyl(3R,4S)-1-acetyl-4-{[(benzyloxy)carbonyl]amino}-piperidin-3-ylcarbamate

The title compound was obtained by reaction of the compound obtained inReferential Example 212 with acetyl chloride and triethylamine inmethylene chloride.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.85-2.15 (2H, m), 2.07 (1.5H, s), 2.14(1.5H, s), 2.75-2.90 (1H, m), 3.10-3.20 (0.5H, m), 3.25-3.35 (0.5H,br.d, J=14.2 Hz), 3.65-4.05 (3H, m), 4.38-4.47 (0.5H, br.d, J=13.0 Hz),4.54-4.63 (0.5H, m), 4.69-4.83 (1H, br), 4.98-5.20 (2.5H, m), 5.90-6.05(0.5H, br), 7.30-7.40 (5H, m).

MS (ESI) m/z: 392 (M+H)⁺.

Referential Example 214 tert-Butyl(3R,4S)-1-acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-ylcarbamate

10% Palladium on carbon (532 mg) was added to a solution of the compound(745 mg) obtained in Referential Example 213 in ethanol (50 ml), and themixture was stirred at room temperature for 16 hours under a hydrogenatmosphere. Insoluble matter was removed by filtration through Celite,and the filtrate was then concentrated under reduced pressure. Theresultant residue was treated with 5-chloroindole-2-carboxylic acid (467mg) in a similar manner to Referential Example 68 to obtain the titlecompound (650 mg).

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 1.60-1.80 (2H, m), 2.12 (1H, s), 2.16(2H, s), 2.30-2.45 (0.5H, m), 2.67-2.82 (0.3H, m), 2.89 (0.7H, d, J=13.7Hz), 3.23 (0.7H, t, J=12.9 Hz), 3.37 (0.3H, d, J=13.7 Hz), 3.81-3.95(1H, m), 4.05-4.33 (2H, m), 4.62-4.72 (0.3H, br), 4.77 (0.7H, d, J=13.7Hz), 5.10-5.27 (1H, m), 6.81 (0.3H, br.s), 6.85 (0.7H, s), 7.21 (1H,br.d, J=8.8 Hz), 7.34 (1H, d, J=8.8 Hz), 7.57 (0.3H, br.s), 7.61 (0.7H,s), 8.55-8.65 (0.5H, br), 9.43-9.53 (0.7H, br), 9.60-9.70 (0.3H, br).

MS (ESI) m/z: 435 (M+H)⁺.

Referential Example 215 Ethyl(3R,4R)-5-azido-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]valerate

The title compound was obtained from the (3R,4S)-compound (high-polarcompound) obtained in Referential Example 168 in a similar manner toReferential Example 210.

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=6.6 Hz), 1.42 (9H, s), 2.51-2.63 (2H,m), 3.43-3.50 (2H, m), 3.84-3.92 (1H, m), 4.03-4.23 (3H, m), 5.10 (2H,s), 5.11-5.24 (1H, m), 5.54-5.60 (1H, m), 7.32-7.44 (5H, m).

Referential Example 216 Benzyl(4R,5R)-5-[(tert-butoxycarbonyl)amino]-2-oxopiperidin-4-ylcarbamate

The title compound was obtained by treating the compound obtained inReferential Example 215 in a similar manner to Referential Example 211.

¹H-NMR (DMSO-d₆) δ: 1.35 (9H, s), 2.19 (1H, dd, J=17.4, 9.1 Hz),2.41-2.51 (1H, m), 2.97 (1H, t, J=9.1 Hz), 3.00-3.11 (1H, m), 3.51-3.64(1H, m), 3.67-3.73 (1H, m), 5.00 (2H, s), 6.71-6.80 (1H, m), 7.20-7.30(5H, m), 7.44-7.52 (1H, m), 8.30 (1H, s).

Referential Example 217 Benzyl(3R,4R)-3-[(tert-butoxycarbonyl)amino]piperidin-4-ylcarbamate

The title compound was obtained by treating the compound obtained inReferential Example 216 in a similar manner to Referential Example 212.

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 2.05 (2H, d, J=12.9 Hz), 2.40 (1H, t,J=11.0 Hz), 2.63 (1H, t, J=12.0 Hz), 3.09 (1H, d, J=12.0 Hz), 3.31 (1H,d, J=11.0 Hz), 3.42-3.53 (2H, m), 4.80-4.91 (1H, m), 5.09 (2H, s),5.23-5.32 (1H, m), 7.34-7.41 (5H, m).

Referential Example 218 tert-Butyl(3R,4R)-1-acetyl-4-{[(benzyloxy)carbonyl]amino}piperidin-3-ylcarbamate

The title compound was obtained by treating the compound obtained inReferential Example 217 in a similar manner to Referential Example 213.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.53-1.67 (1H, m), 1.89-2.00 (1H, m),2.09 (1.5H, s), 2.15 (1.5H, s), 2.57 (1H, t, J=12.0 Hz), 2.78 (1H, t,J=12.0 Hz), 3.20-3.30 (1H, m), 3.40-3.56 (2H, m), 4.23-4.31 (1H, m),4.45-4.56 (1H, m), 5.01-5.08 (1H, m), 5.10 (2H, s), 7.32-7.44 (5H, m).

Referential Example 219 tert-Butyl(3R,4R)-1-acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-ylcarbamate

The title compound was obtained by treating the compound obtained inReferential Example 218 in a similar manner to Referential Example 214.

¹H-NMR (CDCl₃) δ: 1.35 (9H, s), 1.42-1.56 (2H, m), 2.00-2.10 (1H, m),2.12 (1.5H, s), 2.17 (1.5H, s), 2.31-2.43 (1H, m), 2.67-3.00 (1H, m),3.55-3.63 (1H, m), 3.78-4.00 (1H, m), 4.03-4.21 (1H, m), 4.78-5.24 (2H,m), 6.91 (0.5H, s), 6.92 (0.5H, s), 7.22-7.32 (1H, m), 7.33 (1H, d,J=8.8 Hz), 7.58 (1H, s), 9.45 (0.5H, s), 9.51 (0.5H, s).

Referential Example 220 Benzyl(3R,4S)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 212 and methoxyacetyl chloride in a similar mannerto Referential Example 213.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.70-2.15 (2H, m), 2.70-2.85 (1H, m),2.90-3.30 (1H, m), 3.35-3.70 (1H, m), 3.43 (3H, s), 3.75-3.90 (2H, m),3.90-4.25 (3H, m), 4.40-4.80 (1H, m), 5.05-5.09 (1H, m), 5.10 (2H,br.s), 7.30-7.40 (5H, m).

MS (ESI) m/z: 322 (M+H⁺).

Referential Example 221 tert-Butyl(3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 220 in a similar manner to Referential Example 214.

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 1.60-1.80 (1H, m), 2.20-2.40 (1H, m),2.70-2.80 (0.6H, m), 2.90-3.00 (0.4H, m), 3.15-3.30 (0.4H, m), 3.32-3.40(0.6H, m), 3.46, 3.49 (total 3H, each s), 3.85-4.30 (5H, m), 4.55-4.80(1H, m), 5.11 (0.4H, br.s), 6.05 (0.6H, br.s), 6.86 (1H, s), 7.20 (1H,dd, J=8.7, 2.0 Hz), 7.33 (1H, d, J=8.7 Hz), 7.61 (1H, s), 8.40-8.60 (1H,m), 9.41 (1H, br.s).

MS (FAB) m/z: 465 (M+H)⁺.

Referential Example 222 Benzyl(3R,4R)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 217 and methoxyacetyl chloride in a similar mannerto Referential Example 213.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 1.45-1.67 (1H, m), 2.01-2.14 (1H, m),2.63 (1H, t, J=12.0 Hz), 2.75 (1H, t, J=12.0 Hz), 3.20-3.30 (1H, m),3.32-3.41 (5H, m), 3.44-3.56 (2H, m), 4.21-4.32 (1H, m), 4.50-4.63 (1H,m), 5.03-5.08 (1H, m), 5.09 (2H, s), 7.32-7.40 (5H, m).

Referential Example 223 tert-Butyl(3R,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 222 and 5-chloroindole-2-carboxylic acid in asimilar manner to Referential Example 214.

¹H-NMR (CDCl₃) δ: 1.35 (9H, s), 1.41-1.56 (2H, m), 2.11-2.23 (0.5H, m),2.34-2.50 (0.5H, m), 2.78-2.89 (0.5H, m), 3.01-3.12 (0.5H, m), 3.42 (5H,s), 3.45-3.56 (1H, m), 3.78-3.89 (1H, m), 4.00-4.21 (2H, m), 4.78-5.21(2H, m), 6.91 (0.5H, s), 6.93 (0.5H, s), 7.23 (1H, dd, J=8.8, 2.0 Hz),7.33 (1H, d, J=8.8 Hz), 7.59 (1H, s), 9.37 (0.5H, s), 9.54 (0.5H, s).

Referential Example 224 Ethyl(3R,4S)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(diphenyl)silyl]oxy}valerate

Triethylamine (0.47 ml), imidazole (0.19 g) andtert-butylchlorodiphenylsilane (0.7 ml) were successively added to asolution of the (3R,4S)-compound (high-polar compound) (0.74 g) obtainedin Referential Example 168 in N,N-dimethylformamide (30 ml) under icecooling, and the mixture was stirred for 4 days while the temperature ofthe system was gradually raised to room temperature. The reactionmixture was diluted with ethyl acetate and washed with a 10% aqueoussolution of citric acid and saturated aqueous solution of sodiumchloride and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel (hexane:ethylacetate=8:1) to obtain the title compound (0.85 g).

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.19 (3H, t, J=7.4 Hz), 1.40 (9H, s),2.40-2.50 (1H, m), 2.60 (1H, dd, J=15.9, 4.5 Hz), 3.56-3.67 (1H, m),3.74 (1H, dd, J=11.2, 4.5 Hz), 3.78-3.89 (1H, m), 4.08 (2H, q, J=7.4Hz), 4.21-4.30 (1H, m), 4.99-5.13 (3H, m), 5.41-5.52 (1H, m), 7.40-7.53(6H, m), 7.60-7.72 (4H, m).

Referential Example 225 Ethyl(3R,4S)-4-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(5-chloroindol-2-yl)carbonyl]amino}valerate

The title compound was obtained by removing the benzyloxycarbonyl groupof the compound obtained in Referential Example 224 and condensing with5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 214.

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.20 (3H, t, J=7.4 Hz), 1.32 (9H, s),2.40-2.52 (1H, m), 2.71 (1H, dd, J=15.9, 4.5 Hz), 3.67-3.81 (2H, m),4.00-4.20 (2H, m), 4.56-4.74 (1H, m), 5.00-5.11 (1H, m), 6.81 (1H, s),7.21 (1H, dd, J=8.8, 2.0 Hz), 7.32 (1H, d, J=8.8 Hz), 7.40-7.50 (6H, m),7.58 (1H, d, J=8.5 Hz), 7.63-7.74 (5H, m), 9.01-9.14 (1H, m).

Referential Example 226 tert-Butyl(3R*,4R*)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate

The title compound was obtained from the (3R*,4R*)-compound (low-polarcompound) obtained in Referential Example 179 and the compound obtainedin Referential Example 10 in a similar manner to Referential Example 68.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.30-2.37 (2H, m), 2.51 (3H, s),2.82-2.85 (2H, m), 2.92-2.95 (2H, m), 3.17-3.20 (4H, m), 3.40-3.43 (1H,m), 3.69-3.77 (2H, m), 3.97-3.98 (1H, m), 4.98 (1H, br), 5.25 (1H, br).

Referential Example 227N-(3R*,4R*)-4-Amino-1,1-dioxohexahydro-1-thiopyran-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 226 in a similar manner to Referential Example 69.

¹H-NMR (DMSO-d₆) δ: 2.29-2.33 (2H, m), 2.93 (3H, s), 3.16 (2H, br), 3.40(2H, br), 3.52 (2H, br), 3.69-3.76 (3H, m), 4.48 (1H, br), 4.71-4.82(2H, m), 8.34 (2H, br), 8.82 (1H, br).

MS (ESI) m/z: 345 (M+H)⁺.

Referential Example 228 tert-Butyl(3R*,4R*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate

The title compound was obtained from the (3R*,4R*)-compound (low-polarcompound) obtained in Referential Example 179 and5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 68.

¹H-NMR (DMSO-d₆) δ: 1.34 (9H, s), 2.09 (2H, br), 3.07 (1H, d, J=12.6Hz), 3.24-3.28 (1H, m), 3.48 (2H, br), 4.12 (1H, br), 4.53 (1H, br),7.04 (1H, s), 7.16-7.18 (2H, m), 7.44 (1H, d, J=8.7 Hz), 7.67 (1H, s),8.37 (1H, br), 11.81 (1H, s).

MS (ESI) m/z: 442 (M+H)⁺.

Referential Example 229N-[(3R*,4R*)-4-Amino-1,1-dioxohexahydro-1-thiopyran-3-yl]-5-chloroindole-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 228 in a similar manner to Referential Example 69.

¹H-NMR (DMSO-d₆) δ: 2.24-2.33 (2H, m), 3.43-3.55 (3H, m), 3.60-3.66 (1H,m), 3.77 (1H, br), 4.75-4.79 (1H, m), 7.18-7.21 (2H, m), 7.46 (1H, d,J=8.8 Hz), 7.72 (1H, d, J=1.7 Hz), 8.39 (2H, br), 8.58 (1H, d, J=6.8Hz), 11.93 (1H, s).

MS (ESI) m/z: 342 (M+H)⁺.

Referential Example 230 tert-Butyl(3R*,4S*)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate

The title compound was obtained from the (3R*,4S*)-compound (high-polarcompound) obtained in Referential Example 179 and the compound obtainedin Referential Example 10 in a similar manner to Referential Example 98.

¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 2.14-2.24 (1H, m), 2.33-2.38 (1H, m),2.50 (3H, s), 2.78-2.83 (2H, m), 2.86-2.95 (2H, m), 3.08-3.14 (3H, m),3.55 (1H, d, J=13.4 Hz), 3.68 (1H, d, J=15.5 Hz), 3.72 (1H, d, J=15.5Hz), 3.86-3.88 (1H, m), 4.45-4.53 (1H, m), 4.75 (1H, d, J=8.5 Hz), 7.76(1H, d, J=8.3 Hz).

MS (ESI) m/z: 445 (M+H)⁺.

Referential Example 231N-[(3R*,4S*)-4-Amino-1,1-dioxohexahydro-1-thiopyran-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 230 in a similar manner to Referential Example 69.

¹H-NMR (DMSO-d₆) δ: 2.03-2.12 (1H, m), 2.51 (1H, br), 2.93 (3H, s), 3.14(2H, d, J=12.2 Hz), 3.28 (2H, br), 3.33 (2H, br), 3.48 (3H, br), 3.72(2H, br), 4.49 (2H, br), 4.71-4.74 (1H, m), 8.38 (2H, br), 9.21-9.24(1H, m).

MS (ESI) m/z: 345 (M+H)⁺.

Referential Example 232 tert-Butyl(3R*,4R*)-3-{[(5-fluoroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate

The title compound was obtained from the (3R*,4R*)-compound (low-polarcompound) obtained in Referential Example 179 and5-fluoroindole-2-carboxylic acid in a similar manner to ReferentialExample 68.

¹H-NMR (DMSO-d₆) δ: 1.37 (9H, s), 2.10-2.13 (2H, m), 3.06 (1H, br),3.37-3.49 (3H, m), 4.13 (1H, br), 4.57 (1H, br), 6.95-7.01 (2H, m), 7.14(1H, br), 7.30 (1H, d, J=8.5 Hz), 7.41 (1H, dd, J=8.8, 4.5 Hz), 8.28(1H, br), 11.68 (1H, s).

MS (ESI) m/z: 426 (M+H)⁺.

Referential Example 233N-[(3R*,4R*)-4-Amino-1,1-dioxohexahydro-1-thiopyran-3-yl]-5-fluoroindole-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 232 in a similar manner to Referential Example 69.

¹H-NMR (DMSO-d₆) δ: 2.25-2.31 (1H, m), 2.47 (1H, br), 3.30 (1H, br),3.49-3.53 (2H, m), 3.60-3.66 (1H, m), 3.78 (1H, br), 4.79 (1H, br),7.01-7.05 (1H, m), 7.21 (1H, s), 7.38 (1H, d, J=9.0 Hz), 7.44 (1H, dd,J=8.8, 4.4 Hz), 8.40 (2H, br), 8.56 (1H, br), 11.81 (1H, s).

MS (ESI) m/z: 326 (M+H)⁺.

Referential Example 234 Ethyl(3R)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-oxovalerate

Sulfur trioxide-pyridine complex (1.5 g) was gradually added to a mixedsolvent composed of the (3R,4S)-compound (high-polar compound) (0.5 g)obtained in Referential Example 168, dimethyl sulfoxide (6.8 ml) andtriethylamine (2.6 ml), and the mixture was stirred for 20 minutes. Thereaction mixture was poured into water and extracted with ethyl acetate.The resultant organic layer was washed with a saturated aqueous solutionof ammonium chloride, a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride. Theorganic layer was dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1) to obtain the title compound (0.51 g).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.4 Hz), 1.44 (9H, s), 2.51-2.70 (2H,m), 4.01-4.23 (2H, m), 4.45-4.67 (1H, m), 5.00-5.23 (2H, s), 5.24-5.42(1H, m), 7.23-7.43 (5H, m), 9.63 (0.5H, s), 9.67 (0.5H, s).

Referential Example 235 Benzyl(4R)-5-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxopiperidin-4-ylcarbamate

Acetic acid (0.27 ml) and 2 M methylamine (tetrahydrofuran solution, 1.0ml) were successively added to a solution of the compound (0.51 g)obtained in Referential Example 234 in ethanol (10 ml) under icecooling, and the mixture was stirred for 1 hour while the temperature ofthe system was gradually raised to room temperature. Sodiumcyanoborohydride (0.15 g) was added to stir the mixture for 18 hours.The reaction mixture was diluted with chloroform and washed with asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride. The resultant organic layer wasdried over anhydrous sodium sulfate, the solvent was distilled off underreduced pressure, and the resultant residue was dissolved in toluene (20ml). Triethylamine (2 ml) was added to this solution, and the mixturewas heated under reflux for 2 hours. The reaction mixture wasconcentrated under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel(chloroform:methanol=98:2) to obtain the title compound (0.28 g).

¹H-NMR (DMSO-d₆) δ: 1.36 (3.6H, s), 1.38 (5.4H, s), 2.22-2.43 (1H, m),2.44-2.61 (1H, m), 2.72 (1.2H. s), 2.80 (1.8H. s), 3.10 (0.5H, dd,J=12.5, 8.3 Hz), 3.21-3.30 (0.5H, m), 3.33-3.45 (1H, m), 3.56-3.82 (1H,m), 3.89-4.00 (1H, m), 4.94 (1H, d, J=8.1 Hz), 5.00 (1.2H. s), 5.01(0.8H, s), 6.89-7.02 (0.5H, m), 7.23-7.44 (5.5H, m).

Referential Example 236 tert-Butyl(4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-6-oxopiperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 235 and 5-chloroindole-2-carboxylic acid in asimilar manner to Referential Example 214.

¹H-NMR (DMSO-d₆) δ: 1.24 (5.4H, s), 1.35 (3.6H, s), 2.43-2.56 (2H, m),2.80 (3H, s), 3.10-3.20 (1H, m), 3.30-3.52 (1H, m), 3.83-3.91 (0.4H, m),4.02-4.10 (0.6H, m), 4.20-4.31 (0.6H, m), 4.43-4.54 (0.4H, m), 6.94(0.6H, d, J=8.1 Hz), 7.08 (1H, s), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.42(1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.0 Hz), 8.30 (0.4H, s), 8.36 (0.4H,d, J=7.3 Hz), 8.43 (0.6H, d, J=8.3 Hz), 11.75 (0.6H, s), 11.78 (0.4H,s).

Referential Example 237 4-(Pyridin-4-yl)benzoic acid hydrochloride

4-Bromopyridine hydrochloride (11.7 g) and 4-carboxyphenylboric acid(10.0 g) were dissolved in a mixed solvent of toluene (250 ml) and water(250 ml), tetrakis(triphenylphosphine)palladium(0) (5.0 g) and anhydroussodium carbonate (25.4 g) were successively added, and the mixture washeated under reflux at 120° C. for 19 hours. After the reaction mixturewas cooled to room temperature, ethyl acetate was added to the reactionmixture to extract it with water. Concentrated hydrochloric acid wasadded to the water layer to acidify it. The water layer was washed withethyl acetate and then concentrated, and solids deposited were collectedto obtain the title compound (8.37 g).

¹H-NMR (DMSO-d₆) δ: 8.11 (2H, d, J=8.8 Hz), 8.14 (2H, d J=8.8 Hz), 8.35(2H, d, J=6.6 Hz), 8.97 (2H, d, J=6.6 Hz).

MS (FAB) m/z: 200 (M+H)⁺.

Referential Example 238 Methyl 4-(Pyridin-4-yl)benzoate

The compound (12.4 g) obtained in Referential Example 237 was dissolvedin methanol (200 ml), concentrated sulfuric acid (5 ml) was added atroom temperature, and the mixture was heated under reflux for 3 hours.After completion of the reaction, the solvent was distilled off, and asaturated aqueous solution of sodium hydrogencarbonate was added to theresidue to extract it with ethyl acetate. The extract was dried overanhydrous sodium sulfate, the solvent was distilled off, and hexane wasadded to the residue to solidify it, thereby obtaining the titlecompound (9.86 g).

¹H-NMR (CDCl₃) δ: 3.96 (3H, s), 7.54 (2H, d, J=5.9 Hz), 7.71 (2H, dJ=8.3 Hz), 8.16 (2H, d, J=8.3 Hz), 8.71 (2H, d, J=5.9 Hz).

Referential Example 239 4-[4-(Methoxycarbonyl)phenyl]pyridine N-oxide

The compound (1.49 g) obtained in Referential Example 238 was dissolvedin methylene chloride (30 ml), 70% μm-chloroperbenzoic acid (3.46 g) wasadded, and the mixture was stirred at room temperature for 1 hour. Anaqueous solution of sodium sulfite was added to conduct liquidseparation. The resultant organic layer was washed with a saturatedaqueous solution of sodium hydrogencarbonate and then dried overanhydrous sodium sulfate. The solvent was distilled off to obtain thetitle compound (1.33 g).

¹H-NMR (DMSO) δ: 3.88 (3H, s), 7.86 (2H, d, J=7.2 Hz), 7.94 (2H, d,J=8.3 Hz), 8.05 (2H, d, J=8.3 Hz), 8.30 (2H, d, J=7.2 Hz).

MS (FAB) m/z: 230 (M+H)⁺.

Referential Example 240 4-(4-Carboxyphenyl)pyridine N-oxide

The compound (802 mg) obtained in Referential Example 239 was dissolvedin dioxane (20 ml), a 1N aqueous solution (5 ml) of sodium hydroxide wasadded, and the mixture was refluxed for 1 hour and then stirred at roomtemperature for 2 hours. 1N Hydrochloric acid (5 ml) was added toneutralize it. Further, water (5 ml) was added, and precipitate formedwas collected by filtration to obtain the title compound (627 mg).

¹H-NMR (DMSO) δ: 7.85 (2H, d, J=7.2 Hz), 7.91 (2H, d, J=8.3 Hz), 8.03(2H, d, J=8.3 Hz), 8.30 (2H, d, J=7.2 Hz).

Referential Example 241 2-(4-Carboxyphenyl)-1-pyridine N-oxide

The title compound was obtained from 2-bromopyridine in similar mannersto Referential Examples 237, 238, 239 and 240.

¹H-NMR (DMSO-d₆) δ: 7.41-7.45 (2H, m), 7.65-7.69 (1H, m), 7.94 (2H, d,J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz), 8.34-8.38 (1H, m), 13.09 (1H, s).

MS (FAB) m/z: 216 (M+H)⁺.

Referential Example 242 Ethyl 2-(4-chloroanilino)-2-oxoacetate

Triethylamine (1.52 ml) and ethyl chlorooxoacetate (1.11 ml) weresuccessively added to a solution of 4-chloroaniline (1.16 g) inmethylene chloride (26 ml), and the mixture was stirred at roomtemperature for 14 hours. After a saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture to conduct liquidseparation, the resultant organic layer was successively washed with a10% aqueous solution of citric acid and saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. After thesolvent was concentrated under reduced pressure, hexane was added to theresidue to deposit crystals, and the crystals were collected byfiltration and dried to obtain the title compound (1.89 g).

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.1 Hz), 4.42 (2H, q, J=7.1 Hz), 7.34(2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 8.86 (1H, br.s).

MS (ESI) m/z: 228 (M+H)⁺.

Referential Example 243 Methyl2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate

2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51 ml) weredissolved in methylene chloride (26 ml), ethyl chlorooxoacetate (1.10ml) was added to the solution under ice cooling, and the mixture wasstirred at room temperature for 14 hours. After a saturated aqueoussolution of sodium hydrogencarbonate was added to the reaction mixtureto conduct liquid separation, the resultant organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=3:1). The thus-obtained pale yellowsolids were dissolved in methanol (20 ml), and the solution was stirredat 50° C. for 11 hours. The reaction mixture was concentrated underreduced pressure, and crystals deposited were collected by filtrationand dried to obtain the title compound (0.43 g).

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.73 (1H, dd, J=8.8, 2.2 Hz), 8.24 (1H,d, J=8.8 Hz), 8.31 (1H, d, J=2.2 Hz), 9.39 (1H, br.s).

MS (ESI) m/z: 215 (M+H)⁺.

Referential Example 244 (1S)-3-Cyclohexene-1-carboxylic acid

The (R)-(+)-α-methylbenzylamine salt (J. Am. Chem. Soc., Vol. 100, pp.5199-5203, 1978) (95.0 g) of (1S)-3-cyclohexene-1-carboxylic acid wasdissolved in a mixture of ethyl acetate (1.6 l) and 2N hydrochloric acid(1.6 l). After an organic layer was taken out, a water layer wasextracted with ethyl acetate (500 ml×2 times). The resultant organiclayers were combined and washed with saturated aqueous solution ofsodium chloride (300 ml×2 times) to take out an organic layer. After awater layer was extracted with ethyl acetate (200 ml), the resultantorganic layer was washed with saturated aqueous solution of sodiumchloride (100 ml). All organic layers were combined and dried overanhydrous sodium sulfate and then concentrated under reduced pressure toobtain the title compound (48.3 g).

[α]²⁵ _(D)=−104° (c=1, chloroform).

¹H-NMR (CDCl₃) δ: 1.66-1.77 (1H, m), 2.00-2.20 (3H, m), 2.20-2.38 (2H,m), 2.57-2.65 (1H, m), 5.65-5.75 (2H, m).

Referential Example 245 (1S,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one

Iodine (125.4 g) was added to a mixture of the compound (48.0 g)obtained in Referential Example 244, methylene chloride (580 ml),potassium iodide (82.1 g), sodium hydrogencarbonate (42.0 g) and water(530 ml) at an internal temperature of 5° C., and the resultant mixturewas stirred at room temperature for 3 hours. After a 1N aqueous solution(800 ml) of sodium thiosulfate was added to the reaction mixture, theresultant mixture was extracted with methylene chloride (1 L, 500 ml).The resultant organic layer was washed with an aqueous solution (300 ml)of sodium hydrogencarbonate, water (500 ml) and saturated aqueoussolution of sodium chloride (300 ml), dried over anhydrous magnesiumsulfate and then concentrated. Crystals deposited were collected byfiltration, washed with hexane and then dried to obtain the titlecompound (89.5 g).

Mp. 130-131° C.

[α]²⁵ _(D)=−41° (c=1, chloroform).

¹H-NMR (CDCl₃) δ: 1.78-1.96 (2H, m), 2.12 (1H, dd, J=16.5 Hz, 5.2 Hz),2.35-2.50 (2H, m), 2.65-2.70 (1H, m), 2.80 (1H, d, J=12.2 Hz), 4.45-4.55(1H, m), 4.77-4.87 (1H, m).

Referential Example 246 Ethyl(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylate

A 2N aqueous solution (213 ml) of sodium hydroxide was added to anethanol (810 ml) suspension of the compound (89.3 g) obtained inReferential Example 245, and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was concentrated under reducedpressure on a hot bath of 35° C., and water (500 ml) was added to theresultant oil to conduct extraction with methylene chloride (500 ml and300 ml). The extract was washed with water (300 ml) and dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The resultant oil was purified by column chromatography onsilica gel (hexane:ethyl acetate=85:15) to obtain the title compound(41.3 g).

[α]²⁵ _(D)=−58° (c=1, chloroform).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 1.50-1.70 (2H, m), 1.71-1.82(1H, m), 2.08-2.28 (4H, m), 3.16 (2H, s), 4.12 (2H, q, J=7.2 Hz).

Referential Example 247 Ethyl(1S,3R,4R)-3-azido-4-hydroxycyclohexanecarboxylate

A mixture of the compound (41.0 g) obtained in Referential Example 246,N,N-dimethylformamide (300 ml), ammonium chloride (19.3 g) and sodiumazide (23.5 g) was stirred at 76° C. for 13 hours. After insolublematter was taken out by filtration, the filtrate was concentrated underreduced pressure without solidifying, and the product previously takenout by filtration was added to the residue, and the mixture wasdissolved in water (500 ml). The solution was extracted with ethylacetate (500 ml and 300 ml), and the extract was washed with water andsaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and then concentrated to obtain the title compound(51.5 g).

[α]²⁵ _(D)=+8° (c=1, chloroform).

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 1.37-1.64 (3H, m), 1.86-1.95(1H, m), 2.04-2.16 (1H, m), 2.32-2.41 (1H, m), 2.44 (1H, br.s),2.68-2.78 (1H, m), 3.45-3.60 (2H, m), 4.17 (2H, q, J=7.1 Hz).

Referential Example 248 Ethyl(1S,3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxycyclohexanecarboxylate

A mixture of the compound (51.2 g) obtained in Referential Example 247,di-tert-butyl dicarbonate (68.1 g), 5% palladium on carbon (5.0 g) andethyl acetate (1000 ml) was stirred overnight at room temperature undera hydrogen pressure (7 kg/cm²). An oil obtained by filtering thereaction mixture and concentrating the filtrate was purified by columnchromatography on silica gel (hexane:ethyl acetate=4:1→3:1). Thepurified product was crystallized from hexane to obtain the titlecompound (46.9 g). The mother liquor was additionally purified by columnchromatography on silica gel (chloroform:methanol=100:1) to obtain thetitle compound (6.74 g).

[α]²⁵ _(D)=+25° (c=1, chloroform).

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 1.38-1.57 (3H, m), 1.45 (9H,s), 1.86-1.95 (1H, m), 2.05-2.17 (1H, m), 2.29-2.39 (1H, m), 2.61-2.68(1H, m), 3.34 (1H, br.s), 3.39-3.48 (1H, m), 3.53-3.64 (1H, m),4.10-4.24 (2H, m), 4.54 (1H, br.s).

Referential Example 249 Ethyl(1S,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

Methanesulfonyl chloride (42 ml) was added dropwise to a solutioncontaining the compound (53.5 g) obtained in Referential Example 248,methylene chloride (500 ml) and triethylamine (130 ml) over 20 minutesat −10° C. to −15° C. The mixture was heated to room temperature over 2hours and stirred for 2 hours. 0.5N Hydrochloric acid (800 ml) was addeddropwise to the reaction mixture at 0° C. to acidify it, and extractionwas conducted with methylene chloride (500 ml and 300 ml). The resultantorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The crystals thus obtained were dissolved inN,N-dimethylformamide (335 ml), sodium azide (60.5 g) was added, and themixture was stirred at 67° C. to 75° C. for 16 hours. After the reactionmixture was filtered, the filtrate was concentrated under reducedpressure to distill off 250 ml of the solvent. The residue was combinedwith the product previously taken out by filtration, and the mixture wasdissolved in water (500 ml). The solution was extracted with ethylacetate (1 L and 300 ml), and the extract was washed with saturatedaqueous solution of sodium chloride (400 ml and 200 ml), dried overanhydrous magnesium sulfate and then concentrated. The crystals thusobtained were purified by column chromatography on silica gel(hexane:ethyl acetate=4:1) to obtain the title compounds (18.4 g).

[α]²⁵ _(D)=+62° (c=1, chloroform).

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.35-2.00 (15H, s), 2.60-2.68(1H, m), 3.80-3.96 (2H, m), 4.15 (2H, q, J=7.1 Hz), 4.61 (1H, br.s).

Referential Example 250(1S,3R,4S)-4-Azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylicacid

Lithium hydroxide (102 mg) and water (5 ml) were added to a solution ofthe compound (1.0 g) obtained in Referential Example 249 intetrahydrofuran (25 ml). After stirring for 17 hours, lithium hydroxide(50 mg) was additionally added to stir the mixture for 4 hours. 1NHydrochloric acid (6.3 ml) was added to the reaction mixture to conductextraction with ethyl acetate. After the resultant organic layer wasdried, the solvent was distilled off under reduced pressure to obtainthe title compound (980 mg).

¹H-NMR (CDCl₃) δ: 1.30-2.20 (6H, m), 1.45 (9H, s), 2.70-2.80 (1H, m),3.94 (2H, br.s), 4.73 (1H, br.s).

Referential Example 251 tert-Butyl(1R,2S,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The compound (4.77 g) obtained in Referential Example 250 was dissolvedin methylene chloride (150 ml), to which dimethylamine hydrochloride(3.26 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(4.60 g), 1-hydroxybenzotriazole monohydrate (3.24 g) andN-methylmorpholine (8.09 g) were added, and the mixture was stirred atroom temperature for 18 hours. A saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture to conduct liquidseparation. The resultant organic layer was then dried, and the solventwas distilled off under reduced pressure. The resultant residue waspurified by column chromatography on silica gel (methanol:methylenechloride=1:50) to obtain the title compound (4.90 g).

¹H-NMR (CDCl₃) δ: 1.30-1.90 (4H, m), 1.45 (9H, s), 1.97-2.18 (2H, m),2.75-2.85 (1H, m), 2.92 (3H, s), 3.02 (3H, s), 3.68-3.80 (1H, m),4.05-4.20 (1H, m), 4.55-4.75 (1H, m).

Referential Example 252N-{(1R,2S,5S)-2-Azido-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (9.13 g) obtained in Referential Example 251 was dissolvedin methylene chloride (100 ml), and an ethanol solution (100 ml) ofhydrochloric acid was added to stir the mixture at room temperature for1 minute. The reaction mixture was concentrated under reduced pressure,and the resultant residue was dissolved in N,N-dimethylformamide (200ml). To the solution were added the compound (7.75 g) obtained inReferential Example 10, 1-hydroxybenzotriazole monohydrate (4.47 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.2 g) andtriethylamine (2.02 ml), and the mixture was stirred overnight at roomtemperature. The compound (2.38 g) obtained in Referential Example 10and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g)were additionally added to stir the mixture for 3 days. The reactionmixture was concentrated under reduced pressure, and methylene chlorideand a saturated aqueous solution of sodium hydrogencarbonate were addedto the residue to conduct liquid separation. The resultant organic layerwas dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was then purified bycolumn chromatography on silica gel (methylene chloride:methanol=47:3)to obtain the title compound (7.38 g).

¹H-NMR (CDCl₃) δ: 1.72-1.97 (4H, m), 2.10-2.27 (2H, m), 2.51 (3H, s),2.77-3.05 (11H, m), 3.68 (1H, d, J=15.4 Hz), 3.74 (1H, d, J=15.4 Hz),3.86-3.93 (1H, m), 4.54-4.60 (1H, m), 7.25 (1H, d, J=7.6 Hz).

Referential Example 253N-{(1R,2S,5S)-2-Amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

10% Palladium on carbon (6.0 g) was added to a solution of the compound(9.0 g) obtained in Referential Example 252 in methanol (300 ml), andthe mixture was vigorously stirred at room temperature for 11 hoursunder a hydrogen pressure of 4 atm. The catalyst was removed byfiltration, and the filtrate was concentrated under reduced pressure toobtain the title compound (7.67 g).

¹H-NMR (CDCl₃) δ: 1.42-1.54 (1H, m), 1.66-1.89 (5H, m), 2.30-2.40 (1H,m), 2.51 (3H, s), 2.68-3.05 (6H, m), 2.92 (3H, s), 3.00 (3H, s),3.10-3.18 (1H, m), 3.65-3.77 (2H, m), 4.21-4.28 (1H, m), 7.52 (1H, d,J=6.1 Hz).

Referential Example 254 Methyl 2-(4-fluoroanilino)-2-oxoacetate

The title compound was obtained from 4-fluoroaniline and methylchlorooxoacetate in a similar manner to Referential Example 242.

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 7.00-7.14 (2H, m), 7.55-7.68 (2H, m),8.85 (1H, br.s).

MS (ESI) m/z: 198 (M+H)⁺.

Referential Example 255 Methyl 2-(4-bromoanilino)-2-oxoacetate

The title compound was obtained from 4-bromoaniline and methylchlorooxoacetate in a similar manner to Referential Example 242.

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 7.49 (2H, d, J=9.0 Hz), 7.55 (2H, d,J=9.0 Hz), 8.85 (1H, br.s).

MS (FAB) m/z: 258 M⁺.

Referential Example 256 Methyl 2-(4-chloro-2-methylanilino)-2-oxoacetate

The title compound was obtained from 4-chloro-2-methylaniline and methylchlorooxoacetate in a similar manner to Referential Example 242.

¹H-NMR (CDCl₃) δ: 2.31 (3H, s), 3.99 (3H, s), 7.15-7.30 (2H, m), 7.98(1H, d, J=8.8 Hz), 8.77 (1H, br).

MS (FAB) m/z: 228 (M+H)⁺.

Referential Example 257 Methyl2-[(4-chloro-3-methylanilino)-2-oxoacetate

The title compound was obtained from 4-chloro-3-methylaniline and methylchlorooxoacetate in a similar manner to Reference Example 242.

¹H-NMR (CDCl₃) δ: 2.39 (3H, s), 3.98 (3H, s), 7.33 (1H, d, J=12.5 Hz),7.44 (1H, dd, J=12.5, 2.5 Hz), 7.53 (1H, d, J=2.5 Hz), 8.81 (1H, br.s).

MS (ESI) m/z: 228 (M+H)⁺.

Referential Example 258 Methyl 2-(4-chloro-2-fluoroanilino)-2-oxoacetate

The title compound was obtained from 4-chloro-2-fluoroaniline and methylchlorooxoacetate in a similar manner to Referential Example 242.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.15-7.24 (2H, m), 8.33 (1H, t, J=8.4Hz), 9.05 (1H, br.s).

MS (ESI) m/z: 232 (M+H)⁺.

Referential Example 259 Methyl 2-(2,4-difluoroanilino)-2-oxoacetate

The title compound was obtained from 2,4-difluoroaniline and methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 6.87-7.00 (2H, m), 8.29-8.38 (1H, m),8.99 (1H, br.s).

MS (ESI) m/z: 215 M⁺.

Referential Example 260 Methyl 2-(3,4-difluoroanilino)-2-oxoacetate

The title compound was obtained from 3,4-difluoroaniline and methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 7.10-7.28 (2H, m), 7.67-7.78 (1H, m),8.83 (1H, br.s).

MS (ESI) m/z: 215 M⁺.

Referential Example 261 Methyl 2-oxo-2-(pyridin-4-ylamino)acetate

The title compound was obtained from 4-aminopyridine and methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.58 (2H, dd, J=4.8, 1.6 Hz), 8.60 (2H,dd, J=4.8, 1.6 Hz), 9.04 (1H, br.s).

MS (ESI) m/z: 181 (M+H)⁺.

Referential Example 262 Methyl2-[(5-bromopyridin-2-yl)amino]-2-oxoacetate

The title compound was obtained from 2-amino-5-bromopyridine and methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.87 (1H, dd, J=8.8, 2.4 Hz), 8.19 (1H,d, J=8.8 Hz), 8.41 (1H, d, J=2.4 Hz), 9.38 (1H, br.s).

MS (FAB) m/z: 259 M⁺.

Referential Example 263 Ethyl2-[(6-chloropyridin-3-yl)amino]-2-oxoacetate

5-Amino-2-chloropyridine (386 mg) was dissolved in N,N-dimethylformamide(8 ml), and potassium 2-ethoxy-2-oxoacetate (469 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (863 mg) and1-hydroxybenzotriazole monohydrate (203 mg) were added to stir themixture at room temperature for 2 days. After the solvent was distilledoff under reduced pressure, methylene chloride and saturated aqueoussolution of sodium hydrogencarbonate were added to the residue toconduct liquid separation, the resultant organic layer was dried overanhydrous sodium sulfate. After the solvent was concentrated underreduced pressure, the residue was purified by flash columnchromatography on silica gel (hexane:ethyl acetate=2:1) to obtainresidue (200 mg) containing the title compound.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.2 Hz), 4.44 (2H, q, J=7.2 Hz), 7.36(1H, d, J=8.7 Hz), 8.24 (1H, dd, J=8.7, 2.7 Hz), 8.55 (1H, d, J=2.7 Hz),9.03 (1H, br.s).

Referential Example 264 Methyl2-[(6-chloropyridazin-3-yl)amino]-2-oxoacetate

3-Amino-6-chloropyridazine (516 mg) was dissolved in pyridine (26 ml),and triethylamine (665 μl) and methyl chlorooxoacetate (441 μl) weresuccessively added under ice cooling to stir the mixture at roomtemperature for 14 hours. After water was added to the reaction mixtureto conduct liquid separation, the resultant organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain the title compound (748 mg).

¹H-NMR (CDCl₃) δ: 4.03 (3H, s), 7.59 (1H, d, J=9.3 Hz), 8.52 (1H, d,J=9.3 Hz), 9.88 (1H, br.s).

MS (FAB) m/z: 215M⁺.

Referential Example 265 Methyl2-[(5-chlorothiazol-2-yl)amino]-2-oxoacetate

The title compound was obtained from 2-amino-5-chlorothiazole and methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 4.02 (3H, s), 7.48 (1H, s), 11.03 (1H, br.s).

MS (ESI) m/z: 221 (M+H)⁺.

Referential Example 266 Lithium2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate

Water (5.0 ml) and lithium hydroxide (128 mg) were added to a solutionof the compound (1.12 g) obtained in Referential Example 243 intetrahydrofuran (20 ml) at room temperature, and the mixture was stirredfor 5 hours. The solvent was distilled off under reduced pressure,hexane (30 ml) was added to the resultant white solids, and the mixturewas stirred for 30 minutes. The solids were collected by filtration andthen dried to obtain the title compound (1.02 g).

¹H-NMR (DMSO-d₆) δ: 7.90 (1H, dd, J=8.9, 2.6 Hz), 8.12 (1H, d, J=8.9Hz), 8.34 (1H, d, J=2.6 Hz), 10.18 (1H, s).

Referential Example 267 Ethyl 2-(4-chloroanilino)acetate

4-Chloroaniline (2.0 g) was dissolved in acetonitrile (20 ml), and ethylbromoacetate (2.1 g) and potassium carbonate (2.2 g) were added to stirthe mixture at 60° C. for 2 days. The reaction mixture was filteredthrough Celite pad, and the filtrate was concentrated under reducedpressure. The resultant residue was purified by column chromatography onsilica gel (hexane:chloroform=2:1) to obtain the title compound (2.3 g).

¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.3 Hz), 3.86 (2H, s), 4.24 (2H, q,J=7.3 Hz), 4.26-4.35 (1H, m), 6.53 (2H, dd, J=6.6, 2.2 Hz), 7.14 (2H,dd, J=6.6, 2.2 Hz).

Referential Example 268 Ethyl 2-(4-chloro-2-fluoroanilino)acetate

The title compound was obtained from 4-chloro-2-fluoroaniline and ethylbromoacetate in a similar manner to the process described in ReferentialExample 267.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.3 Hz), 3.91 (2H, s), 4.22 (2H, q,J=7.3 Hz), 4.42-4.51 (1H, m), 6.49 (1H, t, J=8.8 Hz), 6.98 (1H, dt,J=8.8, 2.5 Hz), 7.01 (1H, dd, J=11.3, 2.5 Hz).

Referential Example 269 Ethyl2-[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]-2-oxoacetate

The compound (1.5 g) obtained in Referential Example 253 was dissolvedin N,N-dimethylformamide (15 ml), and potassium 2-ethoxy-2-oxoacetate(962 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.18 g) and 1-hydroxybenzotriazole monohydrate (227 mg) were added tostir the mixture at room temperature for 14 hours. After the solvent wasdistilled off under reduced pressure, a saturated aqueous solution ofsodium hydrogencarbonate and methylene chloride were added to theresidue to conduct liquid separation. The resultant organic layer wasdried over anhydrous sodium sulfate. After the solvent was distilled offunder reduced pressure, the residue was purified by flash columnchromatography on silica gel (methylene chloride:methanol=47:3) toobtain the title compound (1.13 g).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.1 Hz), 1.55-2.15 (6H, m), 2.52 (3H,s), 2.77-2.89 (3H, m), 2.94 (5H, br.s), 3.06 (3H, s), 3.71 (1H, d,J=15.5 Hz), 3.73 (1H, d, J=15.5 Hz), 4.06-4.13 (1H, m), 4.32 (2H, q,J=7.1 Hz), 4.60-4.63 (1H, m), 7.39 (1H, d, J=8.3 Hz), 7.83 (1H, d, J=7.6Hz).

MS (ESI) m/z: 466 (M+H)⁺.

Referential Example 270 Lithium2-[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]-2-oxoacetate

The compound (1.13 g) obtained in Referential Example 269 was dissolvedin tetrahydrofuran (20 ml), methanol (10 ml) and water (10 ml), andlithium hydroxide (58 mg) was added to stir the mixture at roomtemperature for 30 minutes. The solvent was distilled off under reducedpressure to obtain the title compound (1.10 g).

¹H-NMR (DMSO-d₆) δ: 1.41-1.73 (4H, m), 2.00-2.07 (2H, m), 2.39 (3H, s),2.74-2.99 (11H, m), 3.67 (2H, s), 3.82-3.88 (1H, m), 4.28-4.30 (1H, m),8.66-8.70 (2H, m).

Referential Example 271N-{(1R,2S,5S)-2-Azido-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 293 and the compound obtained in Referential Example251 in a similar manner to the process described in Referential Example252.

¹H-NMR (CDCl₃) δ: 1.73-1.87 (4H, m), 2.11-2.20 (2H, m), 2.67 (3H, s),2.85-2.90 (1H, m), 2.93 (3H, s), 3.00 (3H, s), 3.90-4.10 (5H, m),4.57-4.62 (1H, m), 7.20-7.22 (1H, m).

MS (FAB) m/z: 378 (M+H)⁺.

Referential Example 272N-{(1R,2S,5S)-2-Amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 271 in a similar manner to the process described inReferential Example 253.

¹H-NMR (CDCl₃) δ: 1.67-1.97 (6H, m), 2.36-2.40 (1H, m), 2.67 (3H, s),2.92 (3H, s), 3.00 (3H, s), 3.07-3.18 (1H, m), 3.92-3.95 (2H, m),4.02-4.06 (2H, m), 4.23-4.26 (1H, m), 7.50-7.52 (1H, m).

Referential Example 273 Methyl 5-chloro-4-fluoroindole-2-carboxylate

Ethanol (100 ml) was added to sodium hydride (content: 60%, 4.7 g) at 0°C. under an argon atmosphere, and the mixture was stirred for 10minutes. After 2-nitropropane (11 ml) was added to the reaction mixtureto stir the mixture for 10 minutes,1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added to stir theresultant mixture at room temperature for 3.5 hours. Precipitate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was partitioned in diethyl ether and water, and anorganic layer was successively washed with a 1N aqueous solution ofsodium hydroxide, water and saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane=3:7) to obtaincrude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oil.Methanol (20 ml) was added to sodium hydride (content: 60%, 1.6 g) at 0°C. under an argon atmosphere, and the mixture was stirred for 10minutes. The reaction mixture was cooled to −20° C., and the crude3-chloro-2-fluorobenzaldehyde (5.5 g) and a solution of methyl2-azidoacetate (5.0 g) in methanol (10 ml) were added within 20 minutes.The temperature of the reaction mixture was raised to 0° C., and afterthe mixture was stirred for 2.5 hours, water (40 ml) was added thereto.The reaction mixture was concentrated under reduced pressure, theresidue was extracted with a mixed solvent of methylene chloride andethyl acetate. The extract was washed with saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off, and the residue was purified by column chromatography onsilica gel (toluene:hexane=3:17) to obtain crude methyl2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g). This product wasdissolved in xylene (50 ml), and the solution was stirred at 130° C. to140° C. for 3 hours. The reaction mixture was concentrated, and theresultant residue was purified by column chromatography on silica gel(methylene chloride) and then crystallized from diethyl ether-hexane toobtain the title compound (440 mg).

¹H-NMR (DMSO-d₆) δ: 4.08 (3H, s), 7.20 (1H, s), 7.31-7.38 (2H, m).

MS (FAB) m/z: 228 (M+H)⁺.

Referential Example 274 5-Chloro-4-fluoroindole-2-carboxylic acid

The compound (440 mg) obtained in Referential Example 273 was dissolvedin tetrahydrofuran (10 ml), an aqueous solution (5 ml) of lithiumhydroxide (160 mg) was added, and the mixture was stirred at roomtemperature for 3 hours. After an aqueous solution (5 ml) of lithiumhydroxide (240 mg) was additionally added to the reaction mixture, andthe mixture was stirred for additional 1 hour, the reaction mixture wasconcentrated under reduced pressure. The residue was neutralized with 1Nhydrochloric acid and extracted 3 times with ethyl acetate. Theresultant organic layers were combined, washed with saturated aqueoussolution of sodium chloride and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (390 mg).

¹H-NMR (DMSO-d₆) δ: 6.79 (1H, s), 7.16-7.26 (2H, m).

MS (FAB) m/z: 214 (M+H)⁺.

Referential Example 275 Ethyl 1-benzyl-5-chloroindole-2-carboxylate

Ethyl 5-chloroindole-2-carboxylate (1.4 g) was dissolved inN,N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) andbenzyl chloride (2.4 ml) were added. The mixture was heated and stirredfor 1.5 hours on a hot bath controlled to 100° C. The reaction mixturewas concentrated under reduced pressure, and the residue was poured intoice water and extracted with ethyl acetate. The resultant organic layerwas washed with saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. The solvent was distilled off, and theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:19) and crystallized from diethyl ether-hexane toobtain the title compound (1.6 g).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.1 Hz), 4.33 (2H, q, J=7.1 Hz), 5.83(2H, s), 7.00-7.02 (2H, d), 7.20-7.38 (6H, m), 7.67 (1H, d, J=1.7 Hz).

Referential Example 276 Ethyl1-benzyl-5-chloro-3-fluoroindole-2-carboxylate

1-Fluoro-2,6-dichloropyridinium triflate (4.4 g) was added to amethylene chloride solution (30 ml) of the compound (2.2 g) obtained inReferential Example 275, and the mixture was heated under reflux for 3days. The reaction mixture was partitioned in ethyl acetate and water,and a water layer was extracted with ethyl acetate. The resultantorganic layers were combined, successively washed with 1N hydrochloricacid, water and saturated aqueous solution of sodium chloride and thendried over anhydrous sodium sulfate. The solvent was distilled off, andthe residue was purified by column chromatography on silica gel (ethylacetate:hexane=1:24) to obtain the crude title compound (2.8 g). A partof this product was purified by preparative thin-layer chromatography onsilica gel to obtain the title compound.

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, t, J=7.1 Hz), 4.29 (2H, q, J=7.1 Hz), 5.77(2H, s), 6.97-6.99 (2H, m), 7.18-7.28 (3H, m), 7.39 (1H, dd, J=9.0, 2.1Hz), 7.69 (1H, dd, J=9.0, 2.1 Hz), 7.78 (1H, d, J=2.1 Hz).

Referential Example 277 Ethyl 5-chloro-3-fluoroindole-2-carboxylate

The crude compound (1.4 g) obtained in Referential Example 276 wasdissolved in anisole (30 ml), and aluminum chloride (2.9 g) was addedportionwise to the solution under ice cooling. The reaction mixture wasstirred at room temperature for 30 minutes, and aluminum chloride (2.9g) was additionally added to stir the mixture for 18 hours. Aluminumchloride (8.0 g) was added to the reaction mixture, and the mixture wasstirred for 5 hours, to which water was added. The reaction mixture wasextracted with ethyl acetate, the resultant organic layers werecombined, successively washed with saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (methylene chloride) to obtain the titlecompound (470 mg).

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.2 Hz), 4.45 (2H, q, J=7.2 Hz),7.25-7.31 (2H, m), 7.66 (1H, d, J=0.73 Hz), 8.53 (1H, br.s).

MS (FAB) m/z: 242 (M+H)⁺.

Referential Example 278 5-Chloro-3-fluoroindole-2-carboxylic acid

The title compound was obtained from the compound obtained inReferential Example 277 in a similar manner to Referential Example 274.

¹H-NMR (DMSO-d₆) δ: 7.31 (1H, dd, J=8.8, 1.9 Hz), 7.42 (1H, dd, J=8.8,1.9 Hz), 7.70 (1H, d, J=1.9 Hz), 11.78 (1H, s)

MS (FAB) m/z: 214 (M+H)⁺.

Referential Example 279 tert-Butyl(1R,2S,5S)-{[(5-chloro-3-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and the compound obtained in Referential Example278 in a similar manner to Referential Example 97.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.73-2.11 (6H, m), 2.65 (1H, br.s), 2.96(3H, s), 3.07 (3H, s), 4.20 (1H, br.s), 4.28 (1H, br.s), 4.78 (1H, br),7.23-7.30 (3H, m), 7.58 (1H, s), 9.03 (1H, s).

MS (FAB) m/z: 481 (M+H)⁺.

Referential Example 280 Ethyl 3-bromo-5-chloroindole-2-carboxylate

N-Bromosuccinimide (440 mg) was added to a solution of ethyl5-chloroindole-2-carboxylate (500 mg) in N,N-dimethylformamide (10 ml).The reaction mixture was stirred at room temperature for 18 hours, andthe solvent was distilled off under reduced pressure. The residue waspartitioned in ethyl acetate and water, and a water layer was extractedwith ethyl acetate. The resultant organic layers were combined, washedwith saturated aqueous solution of sodium chloride and then dried overanhydrous sodium sulfate. The solvent was distilled off, the residue waspurified by column chromatography on silica gel (ethylacetate:hexane=1:9), and white powder thus obtained was washed withhexane to obtain the title compound (680 mg).

¹H-NMR (CDCl₃) δ: 1.42-1.48 (3H, m), 4.43-4.49 (2H, m), 7.30-7.32 (2H,m), 7.65 (1H, d, J=0.74 Hz), 9.11 (1H, s)

MS (FAB) m/z: 303 (M+H)⁺.

Referential Example 281 3-Bromo-5-chloroindole-2-carboxylic acid

The title compound was obtained from the compound obtained inReferential Example 280 in a similar manner to Referential Example 274.

¹H-NMR (DMSO-d₆) δ: 7.35 (1H, dd, J=8.8, 2.0 Hz), 7.48-7.53 (2H, m),12.33 (1H, s)

MS (FAB) m/z: 275 (M+H)⁺.

Referential Example 282 tert-Butyl(1R,2S,5S)-2-{[(3-bromo-5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and the compound obtained in Referential Example281 in a similar manner to Referential Example 97.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.58-2.17 (6H, m), 2.70 (1H, br.s), 2.96(3H, s), 3.07 (3H, s), 4.23-4.28 (2H, m), 4.83 (1H, br), 7.34-7.41 (3H,m), 7.52 (1H, s), 9.76 (1H, s).

MS (FAB) m/z: 542 (M+H)⁺.

Referential Example 283 Ethyl 3-chloro-5-fluoroindole-2-carboxylate

Ethyl 5-fluoroindole-2-carboxylate (2.0 g) was dissolved inN,N-dimethylformamide (20 ml), and a solution of N-chlorosuccinimide(1.4 g) in N,N-dimethylformamide (10 ml) was added dropwise to thesolution under ice cooling. The mixture was stirred at room temperaturefor 18 hours, and the reaction mixture was diluted with ethyl acetateand successively washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride. Theresultant organic layer was then dried over anhydrous sodium sulfate,the solvent was distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel (hexane:ethylacetate=5:1) to obtain the title compound (1.9 g).

¹H-NMR (CDCl₃) δ: 1.45 (3H, t, J=7.4 Hz), 4.46 (2H, q, J=7.4 Hz), 7.14(1H, dt, J=8.0, 2.7 Hz), 7.32-7.36 (2H, m), 8.91 (1H, br).

Referential Example 284 3-Chloro-5-fluoroindole-2-carboxylic acid

The title compound was obtained from the compound obtained inReferential Example 283 in a similar manner to Referential Example 274.

¹H-NMR (DMSO-d₆) δ: 7.20 (1H, dt, J=8.8, 2.4 Hz), 7.31 (1H, dd, J=8.8,2.4 Hz), 7.46 (1H, dd, J=8.8, 4.4 Hz), 12.12 (1H, br).

Referential Example 285 Ethyl 5-chloro-3-formylindole-2-carboxylate

After phosphorus oxychloride (2.0 ml) was added to N-methylformanilide(2.9 g), and the mixture was stirred for 15 minutes, 1,2-dichloroethane(50 ml) and ethyl 5-chloroindole-2-carboxylate (4.0 g) were added, andthe resultant mixture was heated under reflux for 1 hour. The reactionmixture was poured into an aqueous solution (28 ml) of sodium acetate(14 g) under ice cooling. After stirring for 18 hours, insoluble matterwas collected by filtration. This product was successively washed withwater and diethyl ether to obtain the title compound (3.56 g).

¹H-NMR (DMSO-d₆) δ: 1.38 (3H, t, J=7.1 Hz), 4.44 (2H, q, J=7.1 Hz), 7.38(1H, dd, J=8.0, 1.4 Hz), 7.56 (1H, d, J=8.0 Hz), 8.19 (1H, d, J=1.4 Hz),10.53 (1H, s).

Referential Example 286 5-Chloro-3-formylindole-2-carboxylic acid

The compound (1.0 g) obtained in Referential Example 285 was dissolvedin ethanol (10 ml), and a 1N aqueous solution (10 ml) of sodiumhydroxide was added dropwise to stir the mixture at 50° C. for 2 hours.1N Hydrochloric acid (11 ml) was added to the reaction mixture, theresultant mixture was stirred, and insoluble matter was collected byfiltration to obtain the title compound (0.86 g).

¹H-NMR (DMSO-d₆) δ: 7.39 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 8.20(1H, s), 10.58 (1H, s), 12.90 (1H, br).

Referential Example 287 5-Chloro-2-ethoxycarbonylindole-3-carboxylicacid

The compound (1.5 g) obtained in Referential Example 286 and sulfamicacid (1.7 g) were dissolved in tert-butanol (30 ml)-water (30 ml), andsodium chlorite (1.6 g) was added to stir the mixture for 8 hours. Thereaction mixture was diluted with water and extracted with ethylacetate, and the extract was successively washed with 1N hydrochloricacid and saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was recrystallized from a mixed solvent ofisopropyl ether and hexane to obtain the title compound (0.7 g).

¹H-NMR (DMSO-d₆) δ: 1.34 (3H, t, J=7.1 Hz), 4.38 (2H, q, J=7.1 Hz), 7.33(1H, dd, J=8.0, 1.4 Hz), 7.52 (1H, d, J=8.0 Hz), 7.97 (1H, d, J=1.4 Hz),12.75 (1H, br).

Referential Example 288 Ethyl5-chloro-3-[(dimethylamino)carbonyl]indole-2-carboxylate

The compound (0.7 g) obtained in Referential Example 287 was dissolvedin N,N-dimethylformamide (10 ml), and dimethylamine hydrochloride (0.26g), 1-hydroxybenzotriazole monohydrate (0.43 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g) wereadded to stir the mixture at room temperature for 2 days. After thereaction mixture was diluted with ethyl acetate and washed with 1Nhydrochloric acid, a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride inthat order, the resultant organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was recrystallized from a mixed solvent of isopropyl ether andhexane to obtain the title compound (0.6 g).

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.78 (3H, s), 3.04 (3H, s),4.30 (2H, q, J=7.1 Hz), 7.31 (1H, dd, J=8.0, 1.4 Hz), 7.45 (1H, d, J=1.4Hz), 7.48 (1H, d, J=8.0 Hz), 12.29 (1H, s).

Referential Example 2895-Chloro-3-[(dimethylamino)carbonyl]indole-2-carboxylic acid

The title compound was obtained from the compound obtained inReferential Example 288 in a similar manner to Referential Example 286.

¹H-NMR (DMSO-d₆) δ: 2.91 (6H, s), 7.29 (1H, d, J=8.0 Hz), 7.44 (1H, d,J=8.0 Hz), 7.47 (1H, s), 12.16 (1H, s).

Referential Example 2905-(Phenylsulfonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole

Benzenesulfonamide (638 mg) and 4,5-bis(bromomethyl)thiazole (M. Al.Hariri, O. Galley, F. Pautet, H. Fillion, Eur. J. Org. Chem., 1998,593-594.) (1.10 g) were dissolved in N,N-dimethylformamide (10 ml),sodium hydride (60% in oil, 357 mg) was added at a time, and the mixturewas stirred at room temperature for 3 hours. Water and methylenechloride were added to conduct liquid separation. After the resultantorganic layer was dried over anhydrous sodium sulfate, the solvent wasdistilled off, and the residue was purified by column chromatography onsilica gel (methylene chloride:ethyl acetate=9:1) to obtain the titlecompound (137 mg).

¹H-NMR (CDCl₃) δ: 4.60-4.63 (2H, m), 4.70-4.73 (2H, m), 7.52-7.64 (3H,m), 7.88-7.92 (2H, m), 8.71 (1H, s).

MS (FAB) m/z: 267 (M+H)⁺.

Referential Example 291 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazoledihydrobromide

A mixture of the compound (800 mg) obtained in Referential Example 290,phenol (800 μl) and 47% hydrobromic acid (5.00 ml) was heated underreflux for 2 hours. After the reaction mixture was cooled to roomtemperature, ethyl acetate and water were added to conduct liquidseparation. The resultant water layer was concentrated under reducedpressure. Ethyl acetate was added to the residue, precipitate wascollected by filtration to obtain the title compound (521 mg).

¹H-NMR (DMSO-d₆) δ: 4.42 (2H, br.s), 4.56 (2H, br.s), 9.14 (1H, s).

MS (FAB) m/z: 127 (M+H)⁺.

Referential Example 292 5-Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole

The title compound was obtained from the compound obtained inReferential Example 291 in a similar manner to Referential Example 9.

¹H-NMR (CDCl₃) δ: 2.67 (3H, s), 3.95-3.99 (2H, m), 4.01-4.05 (2H, m),8.69 (1H, s).

MS (ESI) m/z: 141 (M+H)⁺.

Referential Example 293 Lithium5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 292 in a similar manner to Referential Example 5.

¹H-NMR (DMSO-d₆) δ: 2.52 (3H, s), 3.73 (2H, t, J=3.2 Hz), 3.87 (2H, t,J=3.2 Hz).

Referential Example 294 tert-Butyl(1R,2S,5S)-2-[(6-chloro-2-naphthoyl)amino]-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and 6-chloronaphthalene-2-carboxylic acid (Eur.J. Chem-Chim. Ther., 1984, Vol. 19, pp. 205-214) in a similar manner toReferential Example 97.

¹H-NMR (CDCl₃) δ: 1.30-2.00 (15H, m), 2.60-2.80 (1H, m), 2.96 (3H, s),3.09 (3H, s), 4.00-4.20 (1H, m), 4.20-4.30 (1H, m), 4.75-4.95 (1H, m),7.44 (1H, d, J=9.0 Hz), 7.70-7.95 (5H, m), 8.31 (1H, s).

MS (FAB) m/z: 474 (M+H)⁺.

Referential Example 295 Ethyl (E)-3-(morpholin-4-yl)-2-acrylate

Ethyl propionate (2.0 ml) was dissolved in methylene chloride (20 ml),and morpholine (1.70 ml) was added dropwise under ice cooling. Afterstirring at room temperature for 1 hour, the reaction mixture wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methylene chloride:methanol=20:1)to obtain the title compound (3.72 g).

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 3.21 (4H, t, J=5.1 Hz), 3.71(4H, t, J=5.1 Hz), 4.14 (2H, q, J=7.1 Hz), 4.70 (1H, d, J=13.4 Hz), 7.36(1H, d, J=13.4 Hz).

MS (FAB) m/z: 186 (M+H)⁺.

Referential Example 296 3-Chlorobenzenediazonium tetrafluoroborate

3-Chloroaniline (2.0 g) was dissolved in a mixed solvent of water (30ml) and concentrated hydrochloric acid (3.5 ml), and sodium nitrite(1.30 g) was added under ice cooling to stir the mixture for 10 minutes.After concentrated hydrochloric acid (5.3 ml) and sodiumtetrafluoroborate (6.90 g) were added to the reaction mixture to stirthe mixture for 30 minutes under ice cooling, precipitate was collectedby filtration and washed with water, methanol and diethyl ether toobtain the title compound (2.63 g). This compound was used in the nextreaction as it was.

Referential Example 297 Ethyl 7-chlorocinnoline-3-carboxylate

The compound (1.45 g) obtained in Referential Example 295 was dissolvedin acetonitrile (100 ml), and the compound (1.73 g) obtained inReferential Example 296 was added. After stirred at room temperature for1 hour, the mixture was heated under reflux for 7 days. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methylene chloride→methylenechloride:ethyl acetate=10:1, then, hexane:ethyl acetate=4:1→1:1) toobtain the title compound (0.25 g).

¹H-NMR (CDCl₃) δ: 1.53 (3H, t, J=7.1 Hz), 4.62 (2H, q, J=7.1 Hz), 7.80(1H, dd, J=8.8, 2.0 Hz), 7.95 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.68 (1H,d, J=2.0 Hz).

Referential Example 298 7-Chlorocinnoline-3-carboxylic acid

The title compound was obtained from the compound obtained inReferential Example 297 in a similar manner to Referential Example 286.

¹H-NMR (DMSO-d₆) δ: 8.02 (1H, dd, J=8.8, 2.0 Hz), 8.34 (1H, d, J=8.8Hz), 8.70 (1H, s), 8.90 (1H, s).

MS (FAB) m/z: 209 (M+H)⁺.

Referential Example 299 tert-Butyl(1R,2S,5S)-2-{[(7-chlorocinnolin-3-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and the compound obtained in Referential Example298 in a similar manner to Referential Example 97.

¹H-NMR (CDCl₃) δ: 1.36 (9H, s), 1.80-2.20 (5H, m), 2.72 (1H, m), 2.96(3H, s), 3.07 (3H, s), 3.49 (1H, d, J=3.7 Hz), 4.30-4.45 (2H, m), 4.87(1H, br), 7.77 (1H, dd, J=8.8, 2.0 Hz), 7.96 (1H, d, J=8.8 Hz), 8.59(2H, br), 8.72 (1H, s).

MS (FAB) m/z: 476 (M+H)⁺.

Referential Example 300 tert-Butyl(1R,2S,5S)-2-{[(5-chloro-1H-benzimidazol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

10% Palladium on carbon (50 mg) was added to a solution of the compound(235 mg) obtained in Referential Example 143 in tetrahydrofuran (5.0ml), and the mixture was stirred overnight at room temperature under ahydrogen atmosphere. To a solution of the product obtained by filteringthe reaction mixture and concentrating the filtrate and5-chlorobenzimidazole-2-carboxylic acid (Bull. Chem. Soc. Jpn., Vol. 62,p. 2668, 1989) (165 mg) in N,N-dimethylformamide (5.0 ml) were added1-hydroxybenzotriazole monohydrate (100 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (171 mg) atroom temperature, and the mixture was stirred for 4 days. Afterconcentrating the reaction mixture, methylene chloride, a saturatedaqueous solution of sodium hydrogencarbonate and water were added toconduct liquid separation, and the resultant water layer was extractedwith methylene chloride. After the resultant organic layers werecombined and dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (methylene chloride:methanol=10:1)to obtain the title compound (250 mg).

¹H-NMR (DMSO-d₆) δ: 1.01-2.00 (6H, m), 1.34 (9H, s), 2.79 (3H, s),2.80-2.95 (1H, m), 2.98 (3H, s), 3.89-4.06 (2H, m), 7.08 (1H, d, J=6.6Hz), 7.31 (1H, d, J=8.5 Hz), 7.62 (2H, br.s), 8.47 (1H, d, J=8.5 Hz),13.46 (1H, br.s).

MS (ESI) m/z: 466 (M+H)⁺.

Referential Example 301 Methyl3-(4-fluorophenyl)-2-{[(4-methylphenyl)sulfonyl]amino}propionate

Methyl 2-amino-3-(4-fluorophenyl)propionate (2.01 g), p-toluenesulfonylchloride (2.25 g) and 4-dimethylaminopyridine (309 mg) were dissolved inchloroform (30 ml), and pyridine (3.0 ml) was added to heat the mixtureunder reflux for 4.5 hours. P-Toluenesulfonyl chloride (2.20 g) wasadditionally added, and the mixture was heated under reflux for 3.5hours. The reaction mixture was poured into ice and 1N hydrochloric acid(17 ml) to conduct liquid separation. The resultant organic layer wassuccessively washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=9:1→2:1) to obtain the titlecompound (2.89 g).

¹H-NMR (CDCl₃) δ: 2.41 (3H, s), 2.90-3.10 (2H, m), 3.51 (3H, s),4.10-4.20 (1H, m), 5.04 (1H, d, J=9.0 Hz), 6.85-6.95 (2H, m), 7.00-7.10(2H, m), 7.20-7.30 (2H, m), 7.60-7.70 (2H, m).

MS (ESI) m/z: 352 (M+H)⁺.

Referential Example 302 Methyl7-fluoro-2-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

The compound (1.50 g) obtained in Referential Example 301 andparaformaldehyde (207 mg) were dissolved in chloroform (40 ml), and thesystem was purged with argon. Trifluoroborane-diethyl ether complex(1.20 ml) was then added, and the mixture was stirred at roomtemperature for 7.5 hours. The reaction mixture was poured into ice anda saturated aqueous solution of sodium hydrogencarbonate to conductliquid separation. The resultant organic layer was then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=3:1) to obtain the title compound (1.45g).

¹H-NMR (CDCl₃) δ: 2.42 (3H, s), 3.15 (2H, d, J=3.9 Hz), 3.46 (3H, s),4.45 (1H, d, J=15.9 Hz), 4.69 (1H, d, J=15.9 Hz), 5.01 (1H, t, J=4.4Hz), 6.70-6.80 (1H, m), 6.80-6.90 (1H, m), 7.00-7.10 (1H, m), 7.29 (2H,d, J=8.1 Hz), 7.72 (2H, d, J=8.3 Hz).

MS (ESI) m/z: 364 (M+H)⁺.

Referential Example 303 Methyl 7-fluoroisoquinoline-3-carboxylate

The compound (1.45 g) obtained in Referential Example 302 was dissolvedin N,N-dimethylformamide (40 ml). Oxygen was introduced into thissolution, and the solution was stirred at 100° C. for 3.5 hours. Afterthe reaction mixture was concentrated under reduced pressure, and asaturated aqueous solution of sodium hydrogencarbonate and methylenechloride were added to the residue to conduct liquid separation, theresultant organic layer was successively washed with a 10% aqueoussolution of citric acid and saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=1:1) to obtainthe title compound (0.59 g).

¹H-NMR (CDCl₃) δ: 4.07 (3H, s), 7.55-7.65 (1H, m), 7.65-7.75 (1H, m),8.00-8.05 (1H, m), 8.61 (1H, s), 9.30 (1H, s).

MS (ESI) m/z: 206 (M+H)⁺.

Referential Example 304 7-Fluoroisoquinoline-3-carboxylic hydrochloride

The compound (1.45 g) obtained in Referential Example 303 was dissolvedin concentrated hydrochloric acid (18 ml), and the solution was heatunder reflux for 2.5 hours. The reaction mixture was cooled, andcrystals were collected by filtration, washed with water and then driedto obtain the title compound (0.46 g).

¹H-NMR (DMSO-d₆) δ: 7.90-8.00 (1H, m), 8.15-8.25 (1H, m), 8.40-8.50 (1H,m), 8.82 (1H, s), 9.55 (1H, s).

MS (FAB) m/z: 192 (M+H)⁺.

Referential Example 305 Ethyl 7-chloro-2H-chromene-3-carboxylate

4-Chloro-2-hydroxybenzaldehyde (Acta. Chem. Scand., Vol. 53, p. 258,1999) (510 mg) was dissolved in tetrahydrofuran (40 ml), sodium hydride(60% in oil, 157 mg) was added, and the mixture was stirred at roomtemperature for 2 hours. A tetrahydrofuran solution (10 ml) of ethyl2-diethylphosphonoacrylate (J. Org. Chem., Vol. 43, P. 1256, 1978) (769mg) was added to the reaction mixture, and the resultant mixture wasstirred at room temperature for 2 hours and then heated overnight underreflux. After the reaction mixture was cooled to room temperature, waterand diethyl ether were added to conduct liquid separation. After theresultant organic layer was dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (hexane:ethylacetate=10:1) to obtain the title compound (247 mg).

¹H-NMR (DMSO-d₆) δ: 1.33 (3H, t, J=7.1 Hz), 4.27 (2H, q, J=7.1 Hz), 4.99(2H, d, J=1.2 Hz), 6.85 (1H, d, J=1.2 Hz), 6.89 (1H, dd, J=8.1, 2.0 Hz),7.04 (1H, d, J=8.1 Hz), 7.38 (1H, d, J=1.0 Hz).

MS (EI) m/z: 238 (M⁺).

Referential Example 306 7-Chloro-2H-chromene-3-carboxylic acid

The title compound was obtained from the compound obtained inReferential Example 305 in a similar manner to Referential Example 274.

¹H-NMR (DMSO-d₆) δ: 4.92 (1H, d, J=2.0 Hz), 6.95 (1H, d, J=2.0 Hz), 7.01(1H, dd, J=8.1, 2.2 Hz), 7.35 (1H, d, J=8.1 Hz), 7.44 (1H, s).

MS (EI) m/z: 210 M⁺.

Referential Example 307 tert-Butyl(1R,2S,5S)-2-{[(E)-3-(4-chlorophenyl)-2-propenoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and 4-chlorocinnamic acid in a similar manner toReferential Example 97.

¹H-NMR (CDCl₃) δ: 1.30-1.55 (3H, m), 1.48 (9H, s), 1.60-2.30 (4H, m),2.57-2.70 (1H, m), 2.95 (3H, s), 3.06 (3H, s), 4.01 (1H, br s),4.10-4.20 (1H, m), 4.78 (1H, br.s), 6.30 (1H, d, J=15.6 Hz), 7.02 (1H,s), 7.31 (2H, d, J=8.5 Hz), 7.40 (2H, d, J=8.5 Hz), 7.52 (1H, d, J=15.6Hz).

MS (ESI) m/z: 450 (M+H)⁺.

Referential Example 308 Methyl6-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate

Dimethyl acetylenedicarboxylate (13.5 ml) was added to a solution of4-chloroaniline (12.76 g) in methanol (150 ml), and the mixture washeated under reflux for 8 hours. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in diphenyl ether (70ml), and the solution was heated under reflux at 240° C. for 4 hours.After cooling the reaction mixture, a mixed solvent of hexane anddiethyl ether was added, and crystals deposited were collected byfiltration and washed to obtain the title compound (11.09 g).

¹H-NMR (DMSO-d₆) δ: 3.97 (3H, s), 7.76 (1H, dd, J=9.0, 2.5 Hz),7.90-8.05 (2H, m), 12.28 (1H, br.s).

MS (ESI) m/z: 238 (M+H)⁺.

Referential Example 309 6-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylicacid

The title compound was obtained from the compound obtained inReferential Example 308 in a similar manner to Referential Example 286.

¹H-NMR (DMSO-d₆) δ: 6.90-7.05 (1H, m), 7.90-8.05 (2H, m), 10.10-10.30(1H, m), 12.13 (1H, br.s).

MS (ESI) m/z: 224 (M+H)⁺.

Referential Example 310 tert-Butyl(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

Water (10 ml) and lithium hydroxide (263 mg) were added to a solution ofthe compound (5.00 g) obtained in Referential Example 97 intetrahydrofuran (40 ml), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, the filtrate wasconcentrated, and 1-hydroxybenzotriazole monohydrate (1.75 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.32 g) anddiisopropylethylamine (11.3 ml) were added to a solution of theresultant residue and dimethylamine hydrochloride (1.85 g) inN,N-dimethylformamide (100 ml) at room temperature. The resultantmixture was stirred for 2 days. After concentrating the reactionmixture, methylene chloride, a saturated aqueous solution of sodiumhydrogencarbonate and water were added to conduct liquid separation. Theresultant water layer was extracted with methylene chloride.

The organic layers were combined and dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressure.The residue was purified by column chromatography on silica gel(methylene chloride:acetone=2:1→1:1) to obtain the title compound (4.59g).

¹H-NMR (CDCl₃) δ: 1.60-1.76 (2H, m), 1.73 (9H, s), 1.76-1.87 (1H, m),1.93 (1H, br.s), 2.14 (1H, br.s), 2.28 (1H, br.s), 2.65 (1H, br.s), 2.95(3H, s), 3.05 (3H, s), 4.01 (1H, br.s), 4.21 (1H, br.s), 4.84 (1H,br.s), 6.81 (1H, br.s), 7.20 (1H, dd, J=8.8, 1.9 Hz), 7.36 (1H, d, J=8.8Hz), 7.59 (1H, br.s), 8.02 (1H, br.s), 10.06 (1H, br.s).

MS (FAB) m/z: 465 (M+H)⁺.

Referential Example 311 tert-Butyl(1R,2S,5S)-2-{[(5-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

1) Ethyl(1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-fluoroindol-2-yl)carbonyl]amino}-cyclohexanecarboxylatewas obtained from the compound obtained in Referential Example 96 and5-fluoroindole-2-carboxylic acid in a similar manner to ReferentialExample 91.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.52 (9H, s), 1.67-2.41 (7H,m), 3.97 (1H, br.s), 4.15 (2H, q, J=7.1 Hz), 4.08-4.22 (1H, m), 6.83(1H, s), 7.00-7.05 (1H, m), 7.32-7.36 (1H, m), 8.02 (1H, s), 9.51 (1H,s).

MS (FAB) m/z: 448 (M+H)⁺.

2) The title compound was obtained from the compound obtained above in asimilar manner to Referential Example 310.

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 1.57-1.79 (2H, m), 1.79-2.00 (2H, m),2.14 (1H, br.s), 2.31 (1H, br.s), 2.65 (1H, br.s), 2.95 (3H, s), 3.07(3H, s), 4.02 (1H, br.s), 4.17-4.25 (1H, m), 4.80 (1H, br.s), 6.82 (1H,br.s), 7.02 (1H, dt, J=2.3, 9.0 Hz), 7.24 (1H, br.s), 7.35 (1H, dd,J=9.0, 4.3 Hz), 7.91 (1H, br.s), 9.49 (1H, br.s).

MS (FAB) m/z: 447 (M+H)⁺.

Referential Example 312 Ethyl2-amino-6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate

After copper(I) cyanide (918 mg) was suspended in tetrahydrofuran (50ml) under an argon atmosphere, and the suspension was cooled to −20° C.,n-butyllithium (1.56 N hexane solution, 6.41 ml) was added dropwise over5 minutes, and the mixture was stirred at −20° C. for 30 minutes. Afterthe reaction mixture was cooled to −50° C., diisobutylaluminum hydride(1.00 M hexane solution) was added dropwise over 20 minutes, and themixture was stirred at −50° C. for 1 hour. A solution of ethyl2,2-dimethyl-5-oxo-5,6-dihydro-2H-pyridine-1-carboxylate (Helv. Chim.Acta, Vol. 81, p. 303, 1998) (986 mg) in tetrahydrofuran (5 ml) wasadded dropwise to the reaction mixture over 5 minutes, and the mixturewas stirred at −50° C. for 2 hours. After raising the temperature of thereaction mixture to −20°, bromine (4.90 ml) was added at a time, and themixture was stirred at −20° C. for 30 minutes. Water and ethyl acetatewere added to the reaction mixture to conduct liquid separation. Theresultant organic layer was washed with a saturated aqueous solution ofsodium sulfite and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was dissolved inN,N-dimethylformamide (10 ml), thiourea (760 mg) was added, and themixture was stirred overnight at 50° C. After the solvent was distilledoff, methylene chloride and a saturated aqueous solution of sodiumhydrogencarbonate were added to conduct liquid separation. The resultantorganic layer was dried over anhydrous sodium sulfate, and the solventwas distilled off. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane=4:1) to obtain the title compound (412mg).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 1.54 (6H, s), 2.65-2.67 (2H,m), 4.09 (2H, q, J=7.1 Hz), 4.44-4.46 (2H, m), 4.78 (2H, br.s)

Referential Example 313 Ethyl2-bromo-6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate

Copper(II) bromide (431 mg) was suspended in acetonitrile (8 ml), andtert-butyl nitrite (249 mg) was added dropwise at room temperature.After an acetonitrile solution (8 ml) of the compound (412 mg) obtainedin Referential Example 312 was added to the reaction mixture under icecooling, the mixture was heated to 50° C. and stirred for 15 minutes.The solvent was distilled off under reduced pressure, and diethyl etherand 10% hydrochloric acid were added to the residue to conduct liquidseparation. The resultant organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (hexane:ethylacetate=6:1) to obtain the title compound (151 mg).

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.55 (6H, s), 2.79-2.81 (2H,m), 4.10 (2H, q, J=7.1 Hz), 4.65-4.67 (2H, m).

MS (ESI) m/z: 319 (M+H)⁺.

Referential Example 314 Ethyl6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]-pyridine-5(4H)-carboxylate

n-Butyllithium (1.56N hexane solution, 1.04 ml) was added to a solutionwith the compound (432 mg) obtained in Referential Example 313 indiethyl ether (5 ml) at −78° C., and the mixture was stirred at −78° C.for 30 minutes. Water and diethyl ether were added to the reactionmixture to conduct liquid separation. The resultant organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff to obtain the title compound (307 mg).

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 1.55 (6H, s), 2.90 (2H, s),4.12 (2H, q, J=7.1 Hz), 4.75 (2H, m), 8.63 (1H, s).

Referential Example 3156,6-Dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine

The compound (307 mg) obtained in Referential Example 314 was dissolvedin a mixed solvent of water (5 ml), ethanol (5 ml) and dioxane (5 ml),and lithium hydroxide (598 mg) was added to this reaction mixture toheat the mixture under reflux for 7 days. After allowing the reactionmixture to cool to room temperature, water and methylene chloride wereadded to conduct liquid separation. The resultant water layer wasextracted 6 times with methylene chloride. The resultant organic layerswere dried over anhydrous sodium sulfate, and the solvent was distilledoff to obtain the title compound (207 mg).

¹H-NMR (CDCl₃) δ: 1.23 (6H, s), 2.71-2.73 (2H, m), 4.09-4.11 (2H, m),8.61 (1H, s).

MS (ESI) m/z: 168 (M⁺).

Referential Example 316 tert-Butyl6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate

The compound (207 mg) obtained in Referential Example 315 was dissolvedin methylene chloride (5 ml), and ditert-butyl dicarbonate (404 mg) and4-(N,N-dimethylamino)pyridine (151 mg) were added to stir the mixture atroom temperature for 2 hours. Di-tert-butyl dicarbonate (404 mg) wasadditionally added, and the mixture was stirred overnight at roomtemperature. Further, di-tert-butyl dicarbonate (1.00 g) was added, andthe mixture was stirred for 1 hour. Methylene chloride and 10%hydrochloric acid were added to conduct liquid separation. The resultantorganic layer was dried over anhydrous sodium sulfate, and the solventwas distilled off. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=4:1) to obtain the title compound (95.4mg).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.52 (6H, s), 2.87 (2H, s), 4.69 (2H,s), 8.62 (1H, s).

MS (ESI) m/z: 269 (M+H)⁺.

Referential Example 317 Lithium4-chloro-5-(1,3-dioxolan-2-yl)thiazole-2-carboxylate

2,4-Dichlorothiazole-5-carbaldehyde ethyleneacetal (J. Chem. Soc. PerkinTrans. 1, 1992, p. 973) (2.26 g) was dissolved in tetrahydrofuran (15ml), and n-butyllithium (1.5N hexane solution, 6.8 ml) was added undercooling with dry ice-acetone to stir the mixture for 20 minutes. At thesame temperature, carbon dioxide was then introduced. The reactionmixture was gradually heated to room temperature over 1.5 hours and thenconcentrated. Hexane was added to the reaction mixture to powder theproduct. The product was collected by filtration and suspended in ethylacetate, and formed powder was collected again by filtration to obtainthe title compound (1.65 g).

Referential Example 318 Ethyl4-chloro-5-(1,3-dioxolan-2-yl)thiazole-2-carboxylate

The compound (242 mg) obtained in Referential Example 317 and ethanol(0.2 ml) were dissolved in N,N-dimethylformamide (2 ml), and1-hydroxybenzotriazole monohydrate (136 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg)were added to stir the mixture at room temperature for a night. Thesolvent was distilled off under reduced pressure, and diethyl ether anddiluted hydrochloric acid were added to separate an organic layer. Theorganic layer was washed with water and a saturated aqueous solution ofsodium hydrogencarbonate and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (170 mg).

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.3 Hz), 4.00-4.10 (2H, m), 4.10-4.20(2H, m), 4.48 (2H, q, J=7.3 Hz), 6.15 (1H, s).

MS (ESI) m/z: 264 (M+H)⁺.

Referential Example 319 Ethyl 4-chloro-5-formylthiazole-2-carboxylate

The compound (132 mg) obtained in Referential Example 318 was dissolvedin diethyl ether (5 ml), and 20% hydrochloric acid (0.3 ml) was added tostir the mixture at room temperature for 7 hours. A saturated aqueoussolution of sodium hydrogencarbonate was added to the reaction mixtureto conduct extraction with diethyl ether. The extract was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (110 mg).

¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J=7.1 Hz), 4.52 (2H, q, J=7.1 Hz), 10.12(1H, s).

Referential Example 320 Ethyl 4-azido-5-formylthiazole-2-carboxylate

The compound (5.15 g) obtained in Referential Example 319 was dissolvedin dimethyl sulfoxide (30 ml), and sodium azide (1.52 g) was added tostir the mixture at room temperature for 2.5 hours. Ice water was addedto the reaction mixture to conduct extraction with diethyl ether.

The extract was washed twice with water and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methylene chloride:methanol=24:1) to obtain the title compound (1.78 g)

¹H-NMR (CDCl₃) δ: 1.45 (3H, t, J=7.1 Hz), 4.50 (2H, q, J=7.1 Hz), 9.95(1H, s).

Referential Example 321 Ethyl6-methyl-6,7-dihydrothiazolo[4,5-d]pyrimidine-2-carboxylate

The compound (1.56 g) obtained in Referential Example 320 was dissolvedin methylene chloride (20 ml), and acetic acid (2 ml), methylamine (2Ntetrahydrofuran solution, 21 ml) and sodium triacetoxyborohydride (2.98g) were added to stir the mixture. After 1 hour, sodiumtriacetoxyborohydride (2.98 g) was additionally added, and the stirringwas continued for additional 4.5 hours. A 0.5N aqueous solution (100 ml)of sodium hydroxide was added to the reaction mixture to alkalify it.After the reaction mixture was extracted with methylene chloride, theextract was dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure to obtain a brown oil (1.43 g).This oil was dissolved in ethanol (50 ml), 10% palladium on carbon (2.0g) was added to conduct hydrogenation at normal temperature andpressure. After 2.5 hours, the catalyst was removed by filtration, andthe filtrate was concentrated. The residue was dissolved in methylenechloride (30 ml), and trimethyl orthoformate (0.7 ml) and borontrifluoride-diethyl ether complex (0.3 ml) were added to stir themixture at room temperature for 15 hours. A saturated aqueous solutionof sodium hydrogencarbonate was added to the reaction mixture to conductextraction with methylene chloride. The extract was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methylene chloride:methanol=97:3) to obtain the title compound (100mg).

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.1 Hz), 2.95 (3H, s), 4.44 (2H, q,J=7.1 Hz), 4.87 (2H, s), 7.06 (1H, s).

MS (ESI) m/z: 226 (M+H)⁺.

Referential Example 322 Lithium6-methyl-6,7-dihydrothiazolo[4,5-d]pyrimidine-2-carboxylate

The compound (463 mg) was dissolved in tetrahydrofuran (20 ml), andlithium hydroxide (54.1 mg) and water (4 ml) were added to stir themixture at room temperature for 4.5 hours. The solvent was distilled offunder reduced pressure, and the residue was dried by means of a vacuumpump to obtain the title compound (460 mg).

¹H-NMR (DMSO-d₆) δ: 2.86 (3H, s), 4.71 (2H, s), 7.03 (1H, s).

Referential Example 323 tert-Butyl(1R,2S,5S)-2-azido-5-{[ethyl(methyl)amino]carbonyl}cyclohexylcarbamate

The title compound was obtained by condensing the compound obtained inReferential Example 250 with ethylmethylamine.

¹H-NMR (CDCl₃) δ: 1.08, 1.18 (total 3H, each t, J=7.1 Hz), 1.46 (9H, s),1.52-1.80 (4H, m), 2.04-2.08 (2H, m), 2.71-2.77 (1H, m), 2.89, 2.98(total 3H, each s), 3.32, 3.39 (total 2H, each q, J=7.1 Hz), 3.74-3.76(1H, m), 4.09-4.11 (1H, m), 4.60 (1H, br.s).

MS (EI) m/z: 326 (M+H)⁺.

Referential Example 324 tert-Butyl(1R,2S,5S)-2-{[(7-chloroisoquinolin-3-yl)carbonyl]amino}-5-{[ethyl(methyl)amino]carbonyl}cyclohexylcarbamate

The compound (1.44 g) obtained in Referential Example 323 was dissolvedin methanol (20 ml), 10% palladium on carbon (150 mg) was added, and themixture was stirred under a hydrogen atmosphere. After 24 hours, thecatalyst was removed by filtration, and the solvent was thenconcentrated under reduced pressure to obtain a colorless oil. This oilwas used in the next reaction as it is.

The above-obtained oil was dissolved in methylene chloride (30 ml), andthe compound (850 mg) obtained in Referential Example 57,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.27 g),1-hydroxybenzotriazole monohydrate (900 mg) and N-methylmorpholine (1.34g) were added to stir the mixture at room temperature. After 17 hours,methylene chloride and a saturated aqueous solution of sodiumhydrogencarbonate were added to the reaction mixture to conduct liquidseparation, and the resultant organic layer was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was subjected to column chromatography on silica gel(methanol:methylene chloride=1:50) to obtain the title compound (1.61g).

¹H-NMR (CDCl₃) δ: 1.10, 1.22 (total 3H, each t, J=7.1 Hz), 1.43 (9H, s),1.84-2.17 (6H, m), 2.66 (1H, br.s), 2.92, 3.03 (total 3H, each s),3.35-3.44 (2H, m), 4.20-4.30 (2H, m), 5.30 (1H, br.s), 7.70 (1H, d,J=8.6 Hz), 7.92 (1H, d, J=8.6 Hz), 8.00 (1H, s), 8.40 (1H, br.s), 8.56(1H, s), 9.03 (1H, s).

MS (FAB) m/z: 489 (M+H)⁺.

Referential Example 325N-((1S,2R,4S)-2-Amino-4-[(7-chloroisoquinolin-3-yl)carbonyl]-4-{[ethyl(methyl)amino]carbonyl}cyclohexyl)-7-chloroisoquinoline-3-carboxamide

The compound (1.60 g) obtained in Referential Example 324 was dissolvedin an ethanol solution (25 ml) of hydrochloric acid, and the solutionwas stirred at room temperature for 30 minutes. The solvent wasdistilled off under reduced pressure, and methylene chloride and a 1Naqueous solution of sodium hydroxide were added to the residue toconduct liquid separation. The resultant water layer was extracted withmethylene chloride, and organic layers were combined and dried overpotassium carbonate. The solvent was distilled off under reducedpressure, hexane was added to the residue, and precipitate was collectedby filtration to obtain the title compound (1.22 g).

¹H-NMR (DMSO-d₆) δ: 1.10, 1.23 (total 3H, each t, J=7.1 Hz), 1.26 (2H,br.s), 1.69-2.11 (6H, m), 2.89 (1H, br.s), 2.93, 3.05 (total 3H, eachs), 3.38-3.45 (2H, m), 3.52 (1H, s), 4.18 (1H, br.s), 7.70 (1H, dd,J=8.8, 2.0 Hz), 7.94 (1H, d, J=8.8 Hz), 8.02 (1H, d, J=2.0 Hz), 8.50(1H, br.s), 8.59 (1H, s), 9.11 (1H, s).

MS (FAB) m/z: 389 (M+H)⁺.

Referential Example 326 Ethyl(1R*,3S*,4S*)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate

The compound (28.0 g) obtained in Referential Example 88 was dissolvedin N,N-dimethylformamide (500 ml), and tert-butyldiphenylsilyl chloride(63.5 ml) and imidazole (19.9 g) were added. After the mixture wasstirred at room temperature for 10 hours, ethyl acetate and water wereadded to the reaction mixture to conduct liquid separation. Theresultant water layer was extracted with ethyl acetate, and organiclayers were combined, washed twice with water and dried over anhydroussodium sulfate. After the solvent was distilled off under reducedpressure, the residue was purified by column chromatography on silicagel (methylene chloride:methanol=1:0→47:3) to obtain the title compound(52.5 g) containing 0.4 molecules of N,N-dimethylformamide.

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.27 (3H, t, J=7.1 Hz), 1.38 (9H, s),1.43-1.59 (3H, m), 1.63-1.67 (1H, m), 1.92-1.98 (1H, m), 2.25-2.32 (1H,m), 2.37-2.42 (1H, m), 3.66 (1H, br.s), 3.80 (1H, br.s), 4.16 (2H, q,J=7.1 Hz), 4.32 (1H, d, J=8.1 Hz), 7.34-7.46 (6H, m), 7.65-7.73 (4H, m).

Referential Example 327 tert-Butyl(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl]oxy}-5-(hydroxymethyl)cyclohexanecarbmate

Lithium aluminum hydride (7.11 g) was suspended in absolute diethylether (100 ml) at 0° C. while purging with argon, and a diethyl ethersolution (500 ml) of the compound (52.5 g) obtained in ReferentialExample 326 was added dropwise over 30 minutes. After stirring at 0° C.for 30 minutes, methanol (100 ml) was added dropwise to the reactionmixture. The resultant slurry was removed by filtration through Celite,and the filtrate was concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=3:1) to obtain thetitle compound (29.6 g).

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.32-1.74 (16H, m), 1.87 (1H, t, J=10.4Hz), 3.35-3.55 (2H, m), 3.71 (1H, br.s), 3.79 (1H, br.s), 4.36 (1H,br.s), 7.34-7.44 (6H, m), 7.65-7.72 (4H, m).

Referential Example 328((1R*,3S*,4S*)-3-[(tert-Butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)methylmethanesulfonate

The compound (29.5 g) obtained in Referential Example 327 was dissolvedin methylene chloride (200 ml) and pyridine (20 ml), and methanesulfonylchloride (9.5 ml) was added to stir the mixture at room temperature for6 hours. The solvent was distilled off under reduced pressure, and ethylacetate and water were added to the residue to conduct liquidseparation. The resultant water layer was extracted with ethyl acetate,and organic layers were combined, washed twice with water and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=2:1) to obtain the title compound(29.8 g).

¹H-NMR (CDCl₃) δ: 1.08 (9H, s), 1.38 (9H, s), 1.43-1.61 (5H, m),1.86-1.89 (2H, m), 3.02 (3H, s), 3.77 (1H, br.s), 3.81 (1H, br.s), 4.10(2H, d, J=5.4 Hz), 4.32 (1H, br.s), 7.35-7.45 (6H, m), 7.64-7.68 (4H,m).

MS (ESI) m/z: 562 (M+H)⁺.

Referential Example 329 tert-Butyl(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl]oxy}-5-(cyanomethyl)cyclohexanecarbamate

The compound (29.8 g) obtained in Referential Example 328 was dissolvedin N,N-dimethylformamide (400 ml), and sodium cyanide (3.64 g) was addedto stir the mixture at 80° C. for 11 hours. Ethyl acetate and asaturated aqueous solution of sodium hydrogencarbonate were added to thereaction mixture to conduct liquid separation. The resultant water layerwas extracted twice with ethyl acetate, and organic layers werecombined, washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=5:1) to obtain thetitle compound (20.6 g).

¹H-NMR (CDCl₃) δ: 1.08 (9H, s), 1.38 (9H, s), 1.43-1.68 (5H, m),1.79-1.85 (1H, m), 1.88-1.95 (1H, m), 2.32 (2H, d, J=7.1 Hz), 3.77 (1H,br.s), 3.82 (1H, br.s), 4.32 (1H, br.d, J=6.8 Hz), 7.35-7.45 (6H, m),7.65-7.71 (4H, m).

Referential Example 330 tert-Butyl(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl]oxy}-5-(2-oxoethyl)cyclohexanecarbamate

The compound (2.00 g) obtained in Referential Example 329 was dissolvedin absolute methylene chloride (20 ml), and the system was purged withargon and then cooled to −78° C. To the solution, was added dropwisediisobutylaluminum hydride (0.95 M hexane solution, 8.55 ml). Thetemperature of the mixture was then allowed to raise to room temperatureand stirred for 3 hours. The reaction mixture was cooled to 0° C., andmethanol (10 ml) was added dropwise. The resultant slurry was removed byfiltration through Celite, and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (methylene chloride:methanol=1:0→49:1) to obtain the titlecompound (1.45 g).

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.38 (9H, s), 1.43-1.54 (5H, m),1.82-1.88 (1H, m), 2.06 (1H, br.s), 2.42-2.43 (2H, m), 3.72 (1H, br.s),3.77 (1H, br.s), 4.38 (1H, br.s), 7.34-7.44 (6H, m), 7.65-7.68 (4H, m),9.77 (1H, t, J=1.7 Hz).

MS (FAB) m/z: 496 (M+H)⁺.

Referential Example 3312-((1R*,3S*,4S*)-3-[(tert-Butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)aceticacid

The compound (8.40 g) obtained in Referential Example 330 was dissolvedin a mixed solvent of water (33 ml) and tert-butanol (120 ml), and2-methyl-2-butene (8.08 ml), sodium dihydrogenphosphate dihydrate (2.64g) and sodium chlorite (3.45 g) were added to stir the mixture at roomtemperature for 1.5 hours. Methylene chloride and water were added tothe reaction mixture to dilute it. The resultant water layer wasadjusted to pH of about 4 with 1N hydrochloric acid. Liquid separationwas conducted, and the resultant water layer was extracted twice withmethylene chloride. Organic layers were combined and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=2:1→1:1) to obtain the title compound(7.62 g).

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.22-1.63 (15H, m), 1.82 (1H, br.s),2.17 (1H, br.s), 2.27-2.33 (1H, m), 3.69 (1H, br.s), 3.84 (1H, br.s),7.00 (1H, br.s), 7.33-7.42 (6H, m), 7.63-7.65 (4H, m).

MS (ESI) m/z: 512 (M+H)⁺.

Referential Example 332 tert-Butyl(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl]oxy}-5-[2-(dimethylamino)-2-oxoethyl]cyclohexanecarbamate

The compound (7.62 g) obtained in Referential Example 331 was dissolvedin N,N-dimethylformamide (150 ml), and dimethylamine hydrochloride (6.07g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.56g), 1-hydroxybenzotriazole monohydrate (1.01 g) and triethylamine (10.3ml) were added to stir the mixture at room temperature for 4 days. Thesolvent was distilled off under reduced pressure, and methylene chlorideand a saturated aqueous solution of sodium hydrogencarbonate were addedto the residue to conduct liquid separation. The resultant organic layerwas extracted with methylene chloride, and organic layers were combinedand dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:1). The solvent wasdistilled off, hexane was added to the residue, and formed whiteprecipitate was collected by filtration to obtain the title compound(6.42 g).

¹H-NMR (CDCl₃) δ: 1.08 (9H, s), 1.38 (9H, br.s), 1.43-1.55 (5H, m),1.79-1.86 (1H, m), 2.03 (1H, br.s), 2.21-2.32 (2H, s), 2.94 (3H, s),3.03 (3H, s), 3.74 (1H, br.s), 3.80 (1H, br.s), 4.49 (1H, br.s),7.33-7.44 (6H, m), 7.64-7.69 (4H, m).

MS (ESI) m/z: 539 (M+H)⁺.

Referential Example 333 tert-Butyl(1R*,2R*,5S*)-5-[2-(dimethylamino)-2-oxoethyl]-2-hydroxycyclohexanecarbamate

The compound (6.36 g) obtained in Referential Example 332 was dissolvedin tetrahydrofuran (50 ml), and tetrabutylammonium fluoride (1Ntetrahydrofuran solution, 17.85 ml) was added to stir the mixture atroom temperature for 13 hours. The solvent was distilled off underreduced pressure, and the residue was purified by flash columnchromatography on silica gel (methylene chloride:methanol=24:1) toobtain the title compound (3.49 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.46-1.60 (4H, m), 1.79-1.84 (2H, m),2.28-2.35 (3H, s), 2.82 (1H, br.s), 2.95 (3H, s), 3.01 (3H, s), 3.56(2H, br.s), 4.67 (1H, br.s).

MS (ESI) m/z: 301 (M+H)⁺.

Referential Example 334((1R*,2R*,4S*)-2-[(tert-Butoxycarbonyl)amino]-4-[2-(dimethylamino)-2-oxoethyl]cyclohexylmethanesulfonate

The compound (8.05 mg) obtained in Referential Example 333 was dissolvedin methylene chloride (50 ml), and the solution was cooled to −78° C.under an argon atmosphere to add dropwise methanesulfonyl chloride (2.70ml). After the temperature of the mixture was allowed to raise to 0° C.and stirred for 30 minutes, it was stirred at room temperature for 2hours. Water was added to the reaction mixture to conduct liquidseparation, and the resultant water layer was extracted with methylenechloride. Organic layers were combined, washed with water and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by flash column chromatography onsilica gel (hexane:ethyl acetate=1:1→0:1) to obtain the title compound(3.63 g).

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.59-1.74 (4H, m), 1.85-2.30 (5H, m),2.95 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 3.79-3.83 (1H, m), 4.72 (1H,br.s), 4.91 (1H, br.s).

MS (ESI) m/z: 379 (M+H)⁺.

Referential Example 335 tert-Butyl(1R*,2S*,5S*)-2-azido-5-[2-(dimethylamino)-2-oxoethyl]cyclohexanecarbamate

The compound (3.62 g) obtained in Referential Example 334 was dissolvedin N,N-dimethylformamide (20 ml), and sodium azide (3.11 g) was added tostir the mixture at 75° C. for 17 hours. The reaction mixture was pouredinto a mixed solvent of water and ethyl acetate to conduct liquidseparation. The resultant water layer was extracted twice with ethylacetate, and organic layers were combined, washed with water, asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by flash column chromatography on silica gel (ethylacetate) to obtain the title compound (1.30 g).

¹H-NMR (CDCl₃) δ: 1.14-1.21 (1H, m), 1.33-1.40 (1H, m), 1.45 (9H, s),1.61-1.71 (1H, m), 1.78-1.91 (3H, m), 2.22-2.27 (3H, m), 2.94 (3H, s),3.00 (3H, s), 3.60-3.62 (1H, m), 3.97 (1H, br.s), 4.76 (1H, br.s).

MS (ESI) m/z: 326 (M+H)⁺.

Referential Example 336N-{(1R*,2S*,4R*)-2-Amino-4-[2-(dimethylamino)-2-oxoethyl]cyclohexyl}-5-chloroindole-2-carboxamidehydrochloride

The title compound was obtained by treating, in a similar manner toReferential Example 69, a product obtained by catalytically reducing thecompound obtained in Referential Example 335 in a similar manner toReferential Example 324 and then condensing it with5-chloroindole-2-carboxylic acid.

¹H-NMR (DMSO-d₆) δ: 1.16-1.19 (1H, m), 1.51-1.56 (1H, m), 1.70-1.73 (1H,m), 1.81-1.91 (2H, m), 1.99-2.03 (1H, m), 2.19-2.30 (3H, m), 2.83 (3H,s), 2.99 (3H, s), 3.63 (1H, br.s), 4.08 (1H, br.s), 7.19 (1H, dd, J=8.7,1.7 Hz), 7.35 (1H, s), 7.44 (1H, d, J=8.7 Hz), 7.69 (1H, d, J=1.7 Hz),8.22 (3H, br.s), 8.62 (1H, d, J=7.1 Hz), 11.91 (1H, s).

MS (ESI) m/z: 377 (M+H)⁺.

Referential Example 337 tert-Butyl(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)cyclohexanecarbamate

The title compound was obtained from the compound obtained inReferential Example 97 in a similar manner to step 2) of ReferentialExample 129.

Referential Example 338((1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)methylmethanesulfonate

The compound (500 mg) obtained in Referential Example 337 andtriethylamine (329 ml) were suspended in tetrahydrofuran (8ml)-methylene chloride (8 ml), and the suspension was cooled to −78° C.After methanesulfonyl chloride (138 ml) was added dropwise to thesuspension, the temperature of the suspension was gradually raised to−5° C., and the suspension was stirred for 15 hours at the sametemperature. After the reaction mixture was concentrated, water wasadded to the residue to conduct extraction 3 times with methylenechloride. The resultant organic layers were washed with saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressureto obtain the title compound (654 mg).

¹H-NMR (CDCl₃) δ: 1.57 (9H, s), 1.84-2.01 (4H, m), 2.28-2.31 (1H, m),3.04 (3H, s), 3.68 (1H, s), 3.74-3.75 (1H, m), 3.91-3.93 (1H, m),4.02-4.12 (2H, m), 4.18-4.20 (1H, m), 4.85 (1H, br.s), 6.81 (1H, s),7.21 (1H, dd, J=2.0, 8.8 Hz), 7.34 (1H, d, J=8.8 Hz), 7.60 (1H, s), 8.02(1H, br.s), 9.27 (1H, br.s).

MS (ESI) m/z: 500 (M+H)⁺.

Referential Example 339 tert-Butyl(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(methylsulfanyl)methyl]cyclohexanecarbamate

The compound (654 mg) obtained in Referential Example 338 was dissolvedin N,N-dimethylformamide (8 ml), and a 15% aqueous solution (1.8 ml) ofsodium thiomethoxide was added to stir the mixture at room temperaturefor 4 hours. The reaction mixture was poured into water and extracted 3times with ethyl acetate. The resultant organic layers were washed withsaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate and then concentrated. The residue was purified by columnchromatography on silica gel (methylene chloride:methanol=24:1) toobtain the title compound (492 mg).

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 1.87-3.04 (13H, m), 3.91-3.94 (1H, m),4.12-4.15 (1H, m), 4.95 (1H, br.s), 6.81 (1H, s), 7.19 (1H, dd, J=8.8,1.2 Hz), 7.35 (1H, d, J=8.8 Hz), 7.57 (1H, s), 9.82 (1H, br.s).

MS (ESI) m/z: 452 (M+H)⁺.

Referential Example 340 tert-Butyl(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(methylsulfonyl)methyl]cyclohexanecarbamate

The compound (300 mg) obtained in Referential Example 339 was dissolvedin methylene chloride (10 ml), and m-chloroperbenzoic acid (70%, 400 mg)was added at 0° C. under stirring. After stirring was continued for 1hour as it is, the reaction mixture was poured into water and extracted3 times with ethyl acetate. The resultant organic layers were washedwith saturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate and then concentrated. After the residue was purified bycolumn chromatography on silica gel (methylene chloride:methanol=24:1),liquid separation was conducted with a saturated aqueous solution ofsodium hydrogencarbonate and ethyl acetate, and the resultant organiclayer was concentrated to obtain the title compound (254 mg).

¹H-NMR (CDCl₃) δ: 1.44-2.19 (13H, m), 2.22-2.30 (2H, m), 2.89-3.25 (7H,m), 3.93-4.15 (2H, m), 4.98 (1H, br.s), 6.82 (1H, s), 7.21 (1H, dd,J=8.8, 2.0 Hz), 7.34 (1H, d, J=8.8 Hz), 7.60 (1H, br.s), 9.54 (1H,br.s).

Referential Example 341 (5-Chlorothien-3-yl)methanol

5-Chlorothiophene-3-carboxylic acid (Monatsh. Chem., Vol. 120, p. 53,1989) (6.93 g) was dissolved in tetrahydrofuran (750 ml), andtriethylamine (27.3 ml) and ethyl chloroformate (18.7 ml) were added tostir the mixture at room temperature for 2.5 hours. An aqueous solution(41 ml) of sodium borohydride (19.3 g) was added dropwise over 10minutes, and the mixture was stirred at room temperature for 18.5 hours.After acetic acid was added to the reaction mixture to acidify it, thesolvent was distilled off under reduced pressure. Water and methylenechloride were added to the residue to conduct liquid separation. Theresultant organic layer was washed with water and a saturated aqueoussolution of sodium hydrogencarbonate. After drying the organic layer,the solvent was distilled off under reduced pressure. The residue waspurified by flash column chromatography on silica gel (ethylacetate:hexane=1:4) to obtain the title compound (5.17 g).

¹H-NMR (CDCl₃) δ: 1.63 (1H, t, J=5.8 Hz), 4.59 (2H, d, J=5.3 Hz), 6.91(1H, d, J=1.7 Hz), 6.98-6.99 (1H, m).

Referential Example 342 5-Chlorothiophene-3-carbaldehyde

The compound (5.17 g) obtained in Referential Example 341 was dissolvedin methylene chloride (400 ml), and manganese dioxide (51.3 g) was addedto stir the mixture at room temperature for 15 hours. After the reactionmixture was filtered, the solvent was distilled off under reducedpressure to obtain the title compound (2.84 g).

¹H-NMR (CDCl₃) δ: 7.35 (1H, d, J=1.7 Hz), 7.88 (1H, d, J=1.7 Hz), 9.75(1H, s).

Referential Example 343 Ethyl 2-azido-3-(5-chlorothien-3-yl)acrylate

After ethanol (15 ml) was added to a 20% ethanol solution (10.7 ml) ofsodium ethoxide, and the mixture was cooled to 0° C., a mixture of thecompound (1.01 g) obtained in Referential Example 342 and ethylazidoacetate (3.55 g) was added dropwise over 30 minutes, and theresultant mixture was stirred at 0° C. for 3 hours. A cooled aqueoussolution of ammonium chloride was added to the reaction mixture toconduct extraction 3 times with diethyl ether. Organic layers werecombined, and the solvent was distilled off under reduced pressure. Theresidue was purified by flash column chromatography on silica gel (ethylacetate:hexane=1:49) to obtain the title compound (1.04 g).

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 4.34 (2H, q, J=7.1 Hz), 6.75(1H, s), 7.39 (1H, d, J=1.7 Hz), 7.54 (1H, d, J=1.7 Hz).

Referential Example 344 Ethyl2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate

The compound (0.97 g) obtained in Referential Example 343 was dissolvedin xylene (20 ml), and the solution was heated under reflux for 30minutes. After allowing the reaction mixture to cool, the solvent wasdistilled off under reduced pressure. Hexane was added to the residue,solids formed were collected by filtration to obtain the title compound(0.608 g).

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.0 Hz), 4.35 (2H, q, J=7.0 Hz), 6.90(1H, s), 7.00 (1H, d, J=1.9 Hz), 9.32 (1H, br).

Referential Example 345 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylicacid

The title compound was obtained from the compound obtained inReferential Example 344 in a similar manner to Referential Example 274.

¹H-NMR (CD₃OD) δ: 3.35 (1H, s), 6.94 (1H, s), 6.96 (1H, s).

MS (ESI) m/z: 200 (M−H)⁻.

Referential Example 346 1-Chloro-4-(2,2-dibromovinyl)benzene

4-Chlorobenzaldehyde (2.81 g) was dissolved in methylene chloride (300ml), and carbon tetrabromide (13.3 g) and triphenylphosphine (21.0 g)were added to stir the mixture at room temperature for 90 minutes. Afterinsoluble matter deposited was removed by filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=20:1) to obtain thetitle compound (5.54 g).

¹H-NMR (CDCl₃) δ: 7.33 (2H, d, J=8.5 Hz), 7.43 (1H, s), 7.47 (2H, d,J=8.5 Hz).

MS (EI) m/z: 296 (M⁺).

Referential Example 347 3-(4-Chlorophenyl)-2-propiolic acid

The compound (1.0 g) obtained in Referential Example 346 was dissolvedin tetrahydrofuran (30 ml), and n-butyllithium (1.59 N hexane solution,4.46 ml) was added dropwise at −78° C. under an argon atmosphere. Thetemperature of the reaction mixture was allowed to raise to roomtemperature and stirred for 1 hour. The reaction mixture was cooledagain to −78° C., stirred for 2 minutes under a carbon dioxideatmosphere and then warmed to room temperature. After the reactionmixture was concentrated under reduced pressure, saturated aqueoussolution of sodium chloride and ethyl acetate were added to the residueto conduct liquid separation. 3N Hydrochloric acid was added to theresultant water layer to acidify it, and extraction was conducted withethyl acetate. The resultant organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain thetitle compound (453 mg).

¹H-NMR (DMSO-d₆) δ: 7.55 (2H, d, J=8.5 Hz), 7.66 (2H, d, J=8.5 Hz),13.90 (1H, br.s).

MS (EI) m/z: 180 (M⁺).

Referential Example 348 Ethyl6-chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylate

Ethyl chlorooxoacetate (2.0 ml) was added to a solution of2-amino-5-chlorobenzamide (2.50 g) in pyridine (15 ml), and the mixturewas stirred at room temperature for 18 hours. The reaction mixture wasconcentrated under reduced pressure, and the resultant residue wasdissolved in acetic acid (50 ml). Acetic anhydride (5.0 ml) was added tothe solution, and the mixture was heated under reflux for 16 hours. Thesolvent was distilled off under reduced pressure, and ethanol was addedto the residue. Crystals deposited were collected by filtration andwashed to obtain the title compound (2.71 g).

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, t, J=7.1 Hz), 4.38 (2H, q, J=7.1 Hz), 7.85(1H, d, J=8.6 Hz), 7.91 (1H, dd, J=8.6, 2.3 Hz), 8.10 (1H, d, J=2.3 Hz),12.85 (1H, br.s).

MS (ESI) m/z: 253 (M+H)⁺.

Referential Example 3496-Chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylic acid

Lithium hydroxide (263 mg) was added to a solution of the compound (1.26g) obtained in Referential Example 348 in a mixed solvent of water (5ml) and tetrahydrofuran (15 ml), and the mixture was stirred at roomtemperature for 18 hours. The reaction mixture was neutralized with 1Nhydrochloric acid (11 ml) under ice cooling and stirred for 1 hour.Crystals deposited were collected by filtration and washed with water toobtain the title compound (0.96 g).

¹H-NMR (DMSO-d₆) δ: 7.50-8.20 (3H, m), 12.44 (1H, br.s).

MS (ESI) m/z: 265 (M+H+CH₃CN)⁺.

Referential Example 350 2-Chloro-N-(4-chlorophenyl)acetamide

p-Chloroaniline (3.82 g) was dissolved in ethyl acetate (30 ml), andchloroacetyl chloride (2.39 ml) was added at room temperature to stirthe mixture for 1 hour. After the reaction mixture was heated andstirred at 60° C. for 3.5 hours, crystals deposited were collected byfiltration to obtain the title compound (4.78 g). The filtrate wasconcentrated to about 1/4, and crystals deposited were collected byfiltration to obtain the title compound (1.01 g).

¹H-NMR (CDCl₃) δ: 4.19 (2H, s), 7.33 (2H, d, J=9.0 Hz), 7.51 (2H, d,J=9.0 Hz), 8.22 (1H, br.s).

Referential Example 351 SodiumS-[2-(4-chloroanilino)-2-oxoethyl]thiosulfate

The compound (5.79 g) obtained in Referential Example 350 was dissolvedin ethanol (140 ml), and an aqueous solution (140 ml) of sodiumthiosulfate pentahydrate (7.04 g) was added at a time at 70° C. to heatthe mixture under reflux for 1.5 hours. The reaction mixture wasconcentrated to about 1/10, and crystals deposited were collected byfiltration to obtain the title compound (8.20 g).

¹H-NMR (DMSO-d₆) δ: 3.73 (2H, s), 7.35 (2H, d, J=8.8 Hz), 7.57 (2H, d,J=8.8 Hz), 10.30 (1H, s).

Referential Example 352 2-Chloro-N-(5-chloropyridin-2-yl)acetamidehydrochloride

2-Amino-5-chloropyridine (3.85 g) was dissolved in ethyl acetate (60ml), and chloroacetyl chloride (2.39 ml) was added at room temperatureto stir the mixture for 1 hour. After the reaction mixture was heatedand stirred at 60° C. for 30 minutes, chloroacetyl chloride (0.5 ml) wasadditionally added, and the mixture was stirred at 60° C. for additional1 hour. Powder deposited was collected by filtration to obtain the titlecompound (6.18 g).

¹H-NMR (DMSO-d₆) δ: 4.36 (2H, s), 7.94 (1H, dd, J=8.8, 2.7 Hz), 8.09(1H, d, J=8.8 Hz), 8.40 (1H, d, J=2.7 Hz), 11.03 (1H, s).

Referential Example 353 SodiumS-{2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl}thiosulfate

An aqueous solution (130 ml) with sodium thiosulfate pentahydrate (6.35g) and sodium hydrogencarbonate (2.15 g) dissolved therein was added toa solution with the compound (6.18 g) obtained in Referential Example352 dissolved in

ethanol (130 ml) at a time at 80° C. under stirring, and the mixture washeated under reflux at 110° C. for 2 hours. The reaction mixture wasconcentrated to solids under reduced pressure, and ethanol (500 ml) wasadded to the residue. The resultant mixture was heated and extractedtwice. The extract was concentrated to about 1/20, and diethyl ether wasadded. Insoluble matter deposited was collected by filtration to obtainthe title compound (6.65 g).

¹H-NMR (DMSO-d₆) δ: 3.77 (2H, s), 7.89 (1H, dd, J=9.0, 2.7 Hz), 8.09(1H, d, J=9.0 Hz), 8.34 (1H, d, J=2.7 Hz), 10.57 (1H, s).

Referential Example 354N-{(1R,2S,5S)-2-[(2-chloroacetyl)amino]-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrathiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (100 mg) obtained in Referential Example 253 was dissolvedin ethyl acetate (10 ml), and chloroacetyl chloride (21.6 μl) was addedto heat and stir the mixture at 60° C. for 30 minutes. After allowingthe reaction mixture to cool, insoluble matter was collected byfiltration and dissolved in methylene chloride-methanol, and the solventwas distilled off under reduced pressure to obtain the crude titlecompound (112 mg).

¹H-NMR (DMSO-d₆) δ: 1.35-1.50 (1H, m), 1.55-2.00 (5H, m), 2.78 (3H, s),2.98 (3H, s), 3.00-3.25 (5H, m), 3.17 (3H, s), 3.80-3.90 (1H, m), 3.96(1H, d, J=12.9 Hz), 4.00-4.15 (1H, m), 4.02 (1H, d, J=12.9 Hz),4.45-4.70 (2H, m), 7.85-8.00 (1H, br), 8.12 (1H, d, J=7.3 Hz), 8.35 (1H,d, J=8.3 Hz).

MS (ESI) m/z: 442 (M+H)⁺.

Referential Example 355 SodiumS-{2-[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrathiazolo[5,4-c]pyridine-2-yl)carbonyl]amino}cyclohexyl)amino]-2-oxoethyl}thiosulfate

The compound (106 mg) obtained in Referential Example 354 was dissolvedin ethanol (1.5 ml), and an aqueous solution (1.5 ml) of sodiumthiosulfate pentahydrate (55 mg) and sodium hydrogencarbonate (18.6 mg)dissolved therein was added at a time at 90° C. under stirring. Theresultant mixture was heated under reflux for 1 hour. The reactionmixture was concentrated to solids under reduced pressure, and ethanol(10 ml) was added to the residue. The resultant mixture was heated andextracted. The extract was concentrated to about 1/2, and isopropylether (10 ml) was added. Insoluble matter deposited was collected byfiltration to obtain the title compound (72 mg).

¹H-NMR (DMSO-d₆) δ: 1.35-1.50 (1H, m), 1.55-1.90 (5H, m), 2.40 (3H, s),2.78 (3H, s), 2.80-3.10 (5H, m), 2.96 (3H, s), 3.44 (1H, d, J=14.2 Hz),3.50 (1H, d, J=14.2 Hz), 3.68 (2H, s), 3.75-3.90 (1H, m), 4.45-4.50 (1H,m), 8.01 (1H, d, J=7.4 Hz), 8.15 (1H, d, J=8.3 Hz).

Referential Example 356 Methyl2-[(5-chlorothien-2-yl)amino]-2-oxoacetate

Triethylamine (1.25 ml) and diphenylphosphoryl azide (1.55 ml) wereadded to a suspension of 5-chlorothiophene-2-carboxylic acid (0.99 g) intoluene (20 ml), and the mixture was stirred at 80° C. for 1 hour. Afterthe reaction mixture was cooled to room temperature, tert-butanol (2 ml)was added, and the mixture was heated under reflux for 19 hours. Thereaction mixture was concentrated under reduced pressure, and methylenechloride (200 ml) was added to the resultant residue. The resultantmixture was successively washed with distilled water, a 10% aqueoussolution of citric acid, distilled water, a saturated aqueous solutionof sodium hydrogencarbonate and saturated aqueous solution of sodiumchloride and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was subjected tocolumn chromatography on silica gel (hexane:ethyl acetate=4:1) to obtaintert-butyl 5-chloro-2-thienylcarbamate (1.05 g).

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 6.21 (1H, d, J=3.1 Hz), 6.60 (1H, d,J=3.1 Hz), 6.91 (1H, br.s).

MS (ESI) m/z: 234 (M+H)⁺.

After the product (1.87 g) obtained above was added to a 4N dioxanesolution (40 ml) of hydrochloric acid, and the mixture was stirred atroom temperature for 4 hours, the solvent was distilled off underreduced pressure. The residue was suspended in tetrahydrofuran (50 ml),and sodium hydrogencarbonate (2.02 g) and methyl chlorooxoacetate (0.883ml) were added under ice cooling to stir the mixture at room temperaturefor 18 hours. After the solvent was distilled off under reducedpressure, and water and methylene chloride were added to the residue toconduct liquid separation, the resultant organic layer was washed withsaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate and then concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (hexane:ethylacetate=3:1), and the solvent was distilled off to obtain the titlecompound (1.44 g).

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 6.61 (1H, d, J=4.2 Hz), 6.75 (1H, d,J=4.2 Hz), 9.42 (1H, br.s).

MS (FAB) m/z: 220 (M+H)⁺.

Referential Example 357 Methyl2-[(5-fluoropyridin-2-yl)amino]-2-oxoacetate

The title compound was obtained from 2-amino-5-fluoropyridine and methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.48-7.53 (1H, m), 8.21 (1H, d, J=2.9Hz), 8.27-8.31 (1H, m), 9.41 (1H, br.s).

MS (FAB) m/z: 198 (M+H)⁺.

Referential Example 358 Methyl2-[4-chloro-2-(trifluoromethyl)anilino]-2-oxoacetate

The title compound was obtained from 4-chloro-2-trifluoroaniline andmethyl chlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 4.01 (3H, s), 7.58 (1H, dd, J=8.8, 2.2 Hz), 7.65 (1H,d, J=2.2 Hz), 8.34 (1H, d, J=8.8 Hz), 9.30 (1H, br.s).

MS (EI) m/z: 281 (M+H)⁺.

Referential Example 3592-[4-Chloro-2-(trifluoromethyl)anilino]-2-oxoacetic acid

Lithium hydroxide (28 mg) was added to a solution of the compound (297mg) obtained in Referential Example 358 in a mixed solvent oftetrahydrofuran (7 ml) and water (3 ml), and the mixture was stirred atroom temperature for 2 hours. 1N Hydrochloric acid (8 ml) and methylenechloride (20 ml) were added to the reaction mixture to conduct liquidseparation. After the resultant organic layer was dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure,and the residue was dried to obtain the title compound (291 mg).

¹H-NMR (CDCl₃) δ: 7.61 (1H, dd, J=8.8, 2.5 Hz), 7.68 (1H, d, J=2.5 Hz),8.26 (1H, d, J=8.8 Hz), 9.36 (1H, br.s).

MS (ESI, anion) m/z: 267 (M−H)⁻

Referential Example 360 5-Chloro-N,N-dimethyl-2-nitrobenzamide

The title compound was obtained by condensing 5-chloro-2-nitrobenzoicacid with dimethylamine in a similar manner to the process described inReferential Example 143.

¹H-NMR (CDCl₃) δ: 2.86 (3H, s), 3.16 (3H, s), 7.38 (1H, d, J=2.2 Hz),7.51 (1H, dd, J=8.8, 2.2 Hz), 8.15 (1H, d, J=8.8 Hz).

Referential Example 361 2-Amino-5-chloro-N,N-dimethylbenzamide

Iron(III) chloride hexahydrate (9.93 g) and zinc powder (8.01 g) wereadded to a solution of the compound (2.8 g) obtained in ReferentialExample 360 in a mixed solvent of N,N-dimethylformamide (80 ml) andwater (40 ml), and the mixture was heated under reflux for 20 minutes.The reaction mixture was filtered through Celite 545, and ethyl acetate(200 ml) was added to the filtrate to conduct liquid separation. Theresultant water layer was washed with ethyl acetate (100 ml×2), andorganic layers were combined, washed with distilled water and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the resultant residue was subjected to columnchromatography on silica gel (methylenechloride:hexane=1:1→1:0→methanol:methylene chloride=1:100) to obtain thetitle compound (2.41 g).

¹H-NMR (CDCl₃) δ: 3.13 (6H, s), 4.33 (2H, br), 6.65 (1H, d, J=8.5 Hz),7.07 (1H, d, J=2.2 Hz), 7.11 (1H, dd, J=8.5, 2.2 Hz).

MS (ESI) m/z: 240 (M+MeCN)⁺.

Referential Example 362 Methyl2-{4-chloro-2-[(dimethylamino)carbonyl]anilino}-2-oxoacetate

The title compound was obtained from the compound obtained inReferential Example 361 and methyl chlorooxoacetate in a similar mannerto the process described in Referential Example 242.

¹H-NMR (CDCl₃) δ: 3.09 (6H, br), 3.96 (3H, s), 7.30 (1H, d, J=2.4 Hz),7.41 (1H, d, J=8.8, 2.4 Hz), 8.34 (1H, d, J=8.8 Hz), 10.46 (1H, br).

MS (ESI) m/z: 285 (M+H)⁺.

Referential Example 363 4-Chloro-2-methoxyaniline

The title compound was obtained from 5-chloro-2-nitroanisole in asimilar manner to the process described in Referential Example 361.

¹H-NMR (CDCl₃) δ: 3.65-3.95 (2H, br), 3.87 (3H, s), 6.61 (1H, d, J=8.8Hz), 6.74-6.78 (2H, m).

MS (ESI) m/z: 199 (M+MeCN+H)⁺.

Referential Example 364 Methyl2-(4-chloro-2-methoxyanilino)-2-oxoacetate

The title compound was obtained from the compound obtained inReferential Example 363 and methyl chlorooxoacetate in a similar mannerto the process described in Referential Example 242.

¹H-NMR (CDCl₃) δ: 3.92 (3H, s), 3.97 (3H, s), 6.90 (1H, d, J=2.2 Hz),6.98 (1H, dd, J=8.8, 2.2 Hz), 8.35 (1H, d, J=8.8 Hz), 9.33-9.44 (1H,br).

MS (ESI) m/z: 244 (M+H)⁺.

Referential Example 365 Ethyl2-(4-chloroanilino)-2-(hydroxyimino)-acetate

The title compound was obtained from 4-chloroaniline (3.03 g) and ethyl2-chloro-2-hydroxyiminoacetate in a similar manner to the processdescribed in literature (Gilchrist, T. L.; Peek, M. E.; Rees, C. W.; J.Chem. Soc. Chem. Commun., 1975, 913).

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.60-1.80 (1H, br), 4.28 (2H,q, J=7.1 Hz), 6.85 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.6 Hz), 8.15-8.45(1H, br).

MS (ESI) m/z: 243 (M+H)⁺.

Referential Example 366 tert-Butyl(1R,2S,5S)-2-{[2-(4-chloroanilino)-2-(hydroxyimino)acetyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The compound (597 mg) obtained in Referential Example 144 was added to asolution of the compound (350 mg) obtained in Referential Example 365 inethanol (5.0 ml), and the mixture was stirred at 70° C. for 3 days.After the reaction mixture was concentrated under reduced pressure, theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=30:1) to obtain the title compound (180 mg).

¹H-NMR (CD₃OD) δ: 1.46 (9H, s), 1.47-1.84 (6H, m), 1.88-1.95 (1H, m),2.90 (3H, s), 3.08 (3H, s), 3.90-3.97 (1H, m), 4.11-4.17 (1H, m), 6.84(2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz).

MS (ESI) m/z: 504 (M+Na)⁺.

Referential Example 367 tert-Butyl(3R,4S)-4-{[2-(4-chloroanilino)-2-oxoacetyl]amino}-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 374 and the compound obtained in Referential Example220 in a similar manner to the process described in Referential Example214.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.55-1.75 (1H, br), 1.94-2.07 (1H, br),2.70-3.00 (1H, m), 3.10-3.37 (1H, m), 3.44 (3H, s), 3.88-4.22 (4H, m),4.55-4.69 (1H, br), 4.80-4.90 (0.5H, br), 5.36-5.48 (0.5H, br),7.20-7.30 (1H, br), 7.32 (2H, d, J=8.8 Hz), 7.62 (2H, d, J=8.8 Hz),8.20-8.40 (1H, br), 9.15-9.25 (1H, br).

MS (ESI) m/z: 469 (M+H)⁺.

Referential Example 368 tert-Butyl(3R,4S)-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 266 and the compound obtained in Referential Example220 in a similar manner to the process described in Referential Example214.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.65-2.30 (2H, br), 2.68-3.02 (1H, m),3.10-3.35 (1H, m), 3.44 (3H, s), 3.80-4.25 (4H, m), 4.45-4.70 (1H, m),5.05-5.20 (0.5H, m), 5.80-5.93 (0.5H, m), 7.30-7.40 (1H, br), 7.71 (1H,br d, J=8.7 Hz), 7.95-8.05 (0.3H, br), 8.19 (1H, br d, J=8.8 Hz), 8.31(1H, br.s), 8.38-8.53 (0.7H, br), 9.74-9.84 (1H, br).

MS (ESI) m/z: 470 (M+H)⁺.

Referential Example 369 tert-Butyl(3R,4S)-4-({2-[(5-bromopyridin-2-yl)amino]-2-oxoacetyl}amino)-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 375 and the compound obtained in Referential Example220 in a similar manner to the process described in Referential Example214.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.50-1.75 (1H, m), 1.95-2.13 (1H, br),2.70-2.98 (1H, m), 3.05-3.36 (1H, m), 3.45 (3H, s), 3.80-4.24 (4H, m),4.57-4.73 (1H, br), 4.85-4.95 (0.25H, br), 5.10-5.15 (0.25H, br),5.45-5.58 (0.5H, br), 7.30-7.38 (1H, m), 7.84 (1H, dd, J=8.8, 2.2 Hz),8.16 (1H, d, J=8.8 Hz), 8.30-8.55 (1H, br), 8.40 (1H, d, J=2.2 Hz), 9.68(1H, br.s).

Referential Example 370 Ethyl 3-(4-chloroanilino)-3-oxopropionate

Potassium ethyl malonate (3.2 g), 1-hydroxybenzotriazole (2.1 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g) weresuccessively added to a solution of 4-chloroaniline (2.0 g) inN,N-dimethylformamide (20 ml) at room temperature, and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate and washed with a saturated aqueous solutionof sodium hydrogencarbonate, a 10% aqueous solution of citric acid andsaturated aqueous solution of sodium chloride. After the resultantorganic layer was dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure to obtain the title compound (4.0g).

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.3 Hz), 3.47 (2H, s), 4.26 (2H, q,J=7.3 Hz), 7.29 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 9.32 (1H,br.s).

Referential Example 371 3-(4-Chloroanilino)-3-oxopropionic acid

A 1N aqueous solution (10 ml) of sodium hydroxide was added dropwise toa solution of the compound (1.0 g) obtained in Referential Example 370in ethanol (10 ml) at room temperature, and the mixture was stirred for2 hours. 1N Hydrochloric acid (10 ml) was added to the reaction mixture,the mixture was stirred, and insoluble matter deposited was thencollected by filtration to obtain the title compound (0.5 g).

¹H-NMR (DMSO-d₆) δ: 3.34 (2H, s), 7.35 (2H, d, J=8.8 Hz), 7.59 (2H, d,J=8.8 Hz), 10.26 (1H, s), 12.66 (1H, br.s).

Referential Example 372 Ethyl 3-(3-chloroanilino)-3-oxopropionate

The title compound was obtained by condensing 3-chloroaniline withpotassium ethyl malonate in a similar manner to the process described inReferential Example 370.

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.3 Hz), 3.47 (2H, s), 4.26 (2H, q,J=7.3 Hz), 7.09 (1H, d, J=8.8 Hz), 7.22-7.26 (1H, m), 7.39 (1H, d, J=8.8Hz), 7.69 (1H, s), 9.35 (1H, br.s).

Referential Example 373 3-(3-Chloroanilino)-3-oxopropionic acid

The title compound was obtained from the compound obtained inReferential Example 372 in a similar manner to the process described inReferential Example 371.

¹H-NMR (DMSO-d₆) δ: 3.35 (2H, s), 7.11 (1H, d, J=8.8 Hz), 7.33 (1H, t,J=8.8 Hz), 7.39 (1H, d, J=8.8 Hz), 7.78 (1H, s), 10.31 (1H, s), 12.67(1H, br.s).

Referential Example 374 2-(4-Chloroanilino)-2-oxoacetic acid

The title compound was obtained from the compound obtained inReferential Example 242 in a similar manner to the process described inReferential Example 359.

¹H-NMR (DMSO-d₆) δ: 7.37 (2H, d, J=8.8 Hz), 7.79 (2H, d, J=8.8 Hz),10.66 (1H, s).

Referential Example 375 2-[(5-Bromopyridin-2-yl)amino]-2-oxoacetic acid

The title compound was obtained from the compound obtained inReferential Example 262 in a similar manner to the process described inReferential Example 359.

¹H-NMR (DMSO-d₆) δ: 7.95-8.00 (1H, m), 8.08 (1H, dd, J=8.8, 2.0 Hz),8.50 (1H, d, J=2.0 Hz), 10.74 (1H, s).

Referential Example 376 4-Chloro-3-fluorobenzoic acid

Sodium chlorite (17 g) was added portionwise to a mixture solutioncomposed of 4-chloro-3-fluorobenzaldehyde (10 g), amidosulfuric acid (18g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, andthe mixture was stirred for 4 days while the temperature of the systemwas gradually raised to room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with water, 1N hydrochloric acidand saturated aqueous solution of sodium chloride. After the resultantorganic layer was dried over anhydrous sodium sulfate, and the solventwas distilled off under reduced pressure, the resultant residue wasrecrystallized from a mixed solvent of diisopropyl ether and hexane toobtain the title compound (11.2 g).

¹H-NMR (DMSO-d₆) δ: 7.72 (1H, dt, J=8.3, 1.5 Hz), 7.77 (1H, dt, J=8.3,1.6 Hz), 7.82 (1H, dt, J=9.7, 1.5 Hz), 13.45 (1H, s).

Referential Example 377 Methyl 2-(4-chloro-3-fluoroanilino)-2-oxoacetate

The title compound was obtained by subjecting the compound obtained inReferential Example 376 to Curtius rearrangement reaction and thencondensing this product with methyl chlorooxoacetate in a similar mannerto the process described in Referential Example 356.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.25-7.27 (1H, m), 7.39 (1H, t, J=8.5Hz), 7.72 (1H, dd, J=10.4, 2.4 Hz), 8.90 (1H, br.s).

Referential Example 378 2-(4-Chloro-3-fluoroanilino)-2-oxoacetic acid

The title compound was obtained from the compound obtained inReferential Example 377 in a similar manner to the process described inReferential Example 359.

¹H-NMR (DMSO-d₆) δ: 7.52 (1H, t, J=8.8 Hz), 7.63 (1H, dd, J=8.8, 2.2Hz), 7.88 (1H, dd, J=12.0, 2.2 Hz), 10.83 (1H, br.s).

Referential Example 379 Ethyl 3-(4-chlorophenyl)-3-oxopropionate

Triethylamine (17 ml) and magnesium chloride (5.5 g) were added to asuspension of potassium ethyl malonate (8.2 g) in ethyl acetate (100 ml)under ice cooling, and the mixture was stirred for 18 hours while thetemperature of the system was gradually raised to room temperature. Onthe other hand, a suspension composed of 4-chlorobenzoic acid (5.0 g),thionyl chloride (12 ml), N,N-dimethylformamide (one drop) and toluene(100 ml) was heated under reflux for 1 hour, and the reaction mixturewas then concentrated. The resultant residue was dissolved in ethylacetate, and the solution was added dropwise to the reaction mixturepreviously prepared under ice cooling. The resultant mixture was stirredfor 18 hours while the temperature of the system was gradually raised toroom temperature. A 10% aqueous solution of citric acid was added to thereaction mixture, and the mixture was stirred for 30 minutes to separatethe resultant organic layer. The organic layer was washed with saturatedaqueous solution of sodium chloride and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was isolated and purified by column chromatography onsilica gel (chloroform) to obtain the title compound (6.4 g).

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.3 Hz), 3.96 (2H, s), 4.21 (2H, q,J=7.3 Hz), 7.46 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz).

Referential Example 380 Ethyl 3-(4-chlorophenyl)-3-hydroxypropionate

Sodium borohydride (0.2 g) was added portionwise under ice cooling to asolution of the compound (1.0 g) obtained in Referential Example 379 intetrahydrofuran (10 ml), and the mixture was stirred for 2 hours whilethe temperature of the system was gradually raised to room temperature.A 10% aqueous solution of citric acid was added to the reaction mixture,and the resultant mixture was extracted with ethyl acetate. Theresultant organic layer was washed with saturated aqueous solution ofsodium chloride and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas isolated and purified by column chromatography on silica gel(chloroform) to obtain the title compound (0.56 g).

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.3 Hz), 2.70 (1H, d, J=7.8 Hz), 2.71(1H, d, J=3.4 Hz), 3.37 (1H, d, J=3.4 Hz), 4.18 (2H, q, J=7.3 Hz),5.09-5.13 (1H, m), 7.30-7.35 (5H, m).

Referential Example 381 3-(4-Chlorophenyl)-3-hydroxypropionic acid

The title compound was obtained from the compound obtained inReferential Example 380 in a similar manner to the process described inReferential Example 359.

¹H-NMR (DMSO-d₆) δ: 3.25-3.32 (1H, m), 4.89-4.95 (1H, m), 5.45-5.53 (1H,m), 7.35-7.36 (5H, m), 12.11-12.18 (1H, m).

MS (ESI, anion) m/z: 198 (M−H)⁻.

Referential Example 382 tert-Butyl(1R,2S,5S)-2-{[3-(4-chlorophenyl)-3-hydroxypropanoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained by condensing the compound obtained inReferential Example 144 with the compound obtained in ReferentialExample 381 in a similar manner to the process described in ReferentialExample 91.

¹H-NMR (CDCl₃) δ: 1.21-1.44 (2H, m), 1.46 (9H, s), 1.76-1.92 (2H, m),1.95-2.10 (2H, m), 2.40-2.55 (2H, m), 2.55-2.68 (1H, m), 2.94 (3H, s),3.05 (3H, s), 3.82-3.96 (1H, m), 4.02-4.17 (1H, m), 4.65-4.80 (2H, m),5.03-5.13 (1H, m), 7.28-7.33 (5H, m).

MS (ESI) m/z: 468 (M+H)⁺.

Referential Example 383 tert-Butyl(1R,2S,5S)-2-{[3-(4-chlorophenyl)-3-oxopropanoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

Manganese dioxide (0.47 g) was added to a solution of the compound (0.5g) obtained in Referential Example 382 in 1,4-dioxane (20 ml) at roomtemperature, and the mixture was stirred for 4 days. Insoluble matterwas removed by filtration through Celite pad, and the resultant filtratewas concentrated under reduced pressure to obtain the title compound(0.46 g).

¹H-NMR (DMSO-d₆) δ: 1.28-1.39 (1H, m), 1.40 (9H, s), 1.41-1.63 (3H, m),2.25-2.42 (2H, m), 2.76 (3H, s), 2.90-2.97 (1H, m), 2.98 (3H, s), 3.56(2H, s), 3.89-3.97 (1H, m), 4.88-4.98 (1H, m), 6.65-6.70 (1H, m),7.30-7.35 (4H, m), 7.33 (1H, dd, J=2.9, 1.7 Hz).

MS (ESI, anion) m/z: 464 (M−H)⁻.

Referential Example 384 Ethyl(1S,3R,4R)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The title compound was obtained from the compound obtained inReferential Example 248 in a similar manner to the process described inReferential Example 249.

[α]_(D) ²⁵+62° (c=1, chloroform)

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.61 (1H, s),1.61-1.71 (2H, m), 1.81-1.90 (1H, m), 1.97-2.03 (1H, m), 2.22-2.28 (1H,m), 2.56-2.60 (1H, m), 3.54 (1H, br.s), 3.63-3.68 (1H, m), 4.16 (2H, q,J=7.1 Hz), 4.58 (1H, br.s).

Referential Example 385 tert-Butyl(1R,2R,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 384 in similar manners to Referential Examples 250and 251.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.40-2.20 (6H, m), 2.70-2.80 (1H, m),2.93 (3H, s), 3.03 (3H, s), 3.60-3.78 (1H, m), 3.83-3.95 (1H, m), 4.65(1H, d, J=7.2 Hz).

Referential Example 386 tert-Butyl(1R,2R,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained by converting the azide group of thecompound obtained in Referential Example 385 into an amino group in asimilar manner to the process described in Referential Example 90 andthen condensing this product with the compound obtained in ReferentialExample 266 in a similar manner to the process described in ReferentialExample 91.

¹H-NMR (CDCl₃) δ: 1.13-2.25 (16H, m), 2.94 (3H, s), 3.03 (3H, s),3.60-3.78 (1H, m), 4.13-4.31 (1H, m), 4.45-4.65 (1H, m), 7.80 (1H, dd,J=8.8, 2.4 Hz), 8.03 (1H, br.s), 8.21 (1H, d, J=8.8 Hz), 8.29 (1H, d,J=2.4 Hz), 9.71 (1H, s).

MS (ESI) m/z: 468 (M+H)⁺.

Referential Example 387N-{(1R,2R,5S)-2-Azido-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 385 and the compound obtained in Referential Example10 in a similar manner to the process described in Referential Example252.

¹H-NMR (CDCl₃) δ: 1.75-2.08 (6H, m), 2.20-2.32 (1H, m), 2.51 (3H, s),2.75-2.97 (4H, m), 2.95 (3H, s), 3.04 (3H, s), 3.65-3.80 (3H, m),4.27-4.39 (1H, m), 7.17-7.28 (1H, m).

MS (ESI) m/z: 392 (M+H)⁺.

Referential Example 388 tert-Butyl4-[(2-methoxy-2-oxoacetyl)amino]piperidine-1-carboxylate

The title compound was obtained from(4-amino-N-tert-butoxycarbonyl)piperidine and methyl chlorooxoacetate ina similar manner to the process described in Referential Example 242.

¹H-NMR (DMSO-d₆) δ: 1.46 (9H, s), 1.34-1.51 (2H, m), 1.89-1.98 (2H, m),2.82-2.96 (2H, m), 3.91 (3H, s), 3.88-4.14 (3H, m), 6.96-7.07 (1H, m).

MS (FAB) m/z: 287 (M+H)⁺.

Referential Example 389 tert-Butyl4-{[2-({(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carboyl]cyclohexyl}amino)-2-oxoacetyl]amino}piperidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 310 and the compound obtained in Referential Example388 in a similar manner to the process described in Referential Example191.

¹H-NMR (DMSO-d₆) δ: 1.46 (9H, s), 1.35-2.28 (11H, m), 2.70-3.18 (9H, m),3.80-4.57 (4H, m), 6.78 (1H, s), 7.15-8.12 (6H, m), 9.45 (1H, s).

MS (FAB) m/z: 617 (M+H)⁺.

Referential Example 390 Methyl2-[(5-chloropyridin-2-yl)(methyl)amino]-2-oxoacetate

The title compound was obtained from 5-chloro-N-methyl-2-pyridineamineand methyl chlorooxoacetate in a similar manner to the process describedin Referential Example 242.

¹H-NMR (CDCl₃) δ: 3.43 (3H, s), 3.81 (3H, s), 7.08 (1H, br.s), 7.68-7.78(1H, m), 8.27 (1H, br.s).

MS (ESI) m/z: 229 (M+H)⁺.

Referential Example 391 Methyl2-[(5-chloropyrimidin-2-yl)amino]-2-oxoacetate

The title compound was obtained from 2-amino-5-chloropyrimidine andmethyl chlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 4.00 (3H, s), 8.63 (2H, s), 9.58 (1H, br.s).

MS (ESI) m/z: 215 (M+H)⁺.

Referential Example 392N-((1R,2S,5S)-2-Azido-5-{[ethyl(methyl)amino]carbonyl}cyclohexyl)-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 323 and the compound obtained in Referential Example293 in a similar manner to the process described in Referential Example252.

¹H-NMR (CDCl₃) δ: 1.08, 1.15 (3H, each t, J=7.1 Hz), 1.74-1.88 (4H, m),2.12-2.22 (2H, m), 2.67 (3H, s), 2.81-2.86 (1H, m), 2.89, 2.96 (3H, eachs), 3.28-3.43 (2H, m), 3.91-4.10 (5H, m), 4.60-4.62 (1H, m), 7.21 (1H,d, J=7.6 Hz).

MS (ESI) m/z: 392 (M+H)⁺.

Referential Example 393 Methyl2-(4-chloro-3-methoxyanilino)-2-oxoacetate

The title compound was obtained by reducing 2-chloro-5-nitroanisole in asimilar manner to the process described in Referential Example 361 intoan amino derivative and then condensing the amino derivative with methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 3.93 (3H, s), 3.98 (3H, s), 7.00 (1H, dd, J=8.5, 2.4Hz), 7.33 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2.4 Hz), 8.89 (1H, br.s).

Referential Example 394 2-(4-Chloro-3-methoxyanilino)-2-oxoacetic acid

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 393 in a similar manner to the process described inReferential Example 359.

¹H-NMR (DMSO-d₆) δ: 3.81 (3H, s), 7.36 (1H, d, J=8.7 Hz), 7.43 (1H, d,J=8.7 Hz), 7.65 (1H, d, J=2.2 Hz), 10.79 (1H, s).

MS (ESI, anion) m/z: 228 (M−H)⁻.

Referential Example 395N¹-{(1S,2R,4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N²-(4-chloro-3-methoxyphenyl)ethanediamide

The title compound was obtained by condensing the compound obtained inReferential Example 144 with the compound obtained in ReferentialExample 394 in a similar manner to the process described in ReferentialExample 97, treating this product with hydrochloric acid in a similarmanner to the process described in Referential Example 69 and thenneutralizing it with a 1N aqueous solution of sodium hydroxide.

¹H-NMR (CDCl₃) δ: 1.48-2.00 (8H, m), 2.84-2.93 (1H, m), 2.95 (3H, s),3.08 (3H, s), 3.33-3.35 (1H, m), 3.89-3.94 (4H, m), 7.06 (1H, dd, J=8.5,2.2 Hz), 7.32 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.2 Hz), 8.05 (1H, d,J=8.5 Hz), 9.43 (1H, br.s).

MS (ESI) m/z: 397 (M⁺).

Referential Example 396 Methyl 2-(4-ethynylanilino)-2-oxoacetate

The title compound was obtained from 4-ethynylaniline and methylchlorooxoacetate in a similar manner to the process described inReferential Example 242.

¹H-NMR (CDCl₃) δ: 3.09 (1H, s), 3.98 (3H, s), 7.50 (2H, d, J=8.4 Hz),7.62 (2H, d, J=8.4 Hz), 8.89 (1H, br.s).

Referential Example 397 Sodium 2-(4-ethynylanilino)-2-oxoacetate

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 396 with sodium hydroxide in a similar manner to theprocess described in Referential Example 266.

¹H-NMR (DMSO-d₆) δ: 4.06 (1H, s), 7.39 (2H, d, J=8.4 Hz), 7.80 (2H, d,J=8.4 Hz), 10.33 (1H, br.s).

Referential Example 398 Methyl2-[(5-chloropyrazin-2-yl)amino]-2-oxoacetate

The title compound was obtained from 2-amino-5-chloropyrazinesynthesized in accordance with literature (Sato, Nobuhiro et al., J.Heterocycl. Chem., 1982, 19(3), 673-4) and methyl chlorooxoacetate in asimilar manner to the process described in Referential Example 242.

¹H-NMR (CDCl₃) δ: 4.02 (3H, s), 8.35 (1H, d, J=1.5 Hz), 9.37 (1H, d,J=1.5 Hz), 9.41 (1H, br.s).

MS (FAB) m/z: 216 (M+H)⁺.

Referential Example 399 2-[(5-Chloropyrazin-2-yl)amino]-2-oxoacetic acid

The title compound was obtained from the compound obtained inReferential Example 398 in a similar manner to the process described inReferential Example 359.

¹H-NMR (DMSO-d₆) δ: 8.62 (1H, s), 9.02 (1H, br.s), 11.30 (1H, s).

MS (EI) m/z: 201 M⁺.

Referential Example 400 2-(4-Chloro-3-nitroanilino)-2-oxoacetic acid

The title compound was obtained by condensing 4-chloro-3-nitroanilinewith methyl chlorooxoacetate in a similar manner to the processdescribed in Referential Example 242 and then hydrolyzing this productin a similar manner to the process described in Referential Example 359.

¹H-NMR (DMSO-d₆) δ: 7.76 (1H, dd, J=8.8 Hz), 8.04 (1H, dd, J=8.8, 2.4Hz), 8.55 (1H, d, J=2.4 Hz), 11.24 (1H, s).

No proton attributable to the carboxylic acid was observed.

MS (EI) m/z: 244 M⁺.

Referential Example 401 Sodium 2-(4-chloro-2-nitroanilino)-2-oxoacetate

The title compound was obtained by condensing 4-chloro-2-nitroanilinewith methyl chlorooxoacetate in a similar manner to the processdescribed in Referential Example 242, hydrolyzing this product in asimilar manner to the process described in Referential Example 266,dissolving the resultant residue in methanol, adding a 1N aqueoussolution of sodium hydroxide and collecting precipitate formed byfiltration.

¹H-NMR (DMSO-d₆) δ: 7.84 (1H, dd, J=9.0, 2.5 Hz), 8.20 (1H, d, J=2.5Hz), 8.67 (1H, d, J=9.0 Hz), 11.89 (1H, s).

Referential Example 402 6-Chloro-4-methyl-3-pyridineamine

2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in ethanol (5ml), and a catalytic amount of Raney nickel catalyst was added to stirthe mixture at room temperature for 9 hours under a hydrogen atmosphere.The catalyst was removed by filtration, and the solvent was distilledoff under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=3:2) to obtain thetitle compound (113 mg).

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 3.85 (2H, br.s), 6.96 (1H, s), 7.74 (1H,s).

MS (EI) m/z: 142 M⁺.

Referential Example 403 N¹-(2-Aminophenyl)-N²-(4-chlorophenyl)ethanamide

The title compound was obtained by condensing 1,2-benzenediamine withthe compound obtained in Referential Example 374 in a similar manner tothe process described in Referential Example 59.

¹H-NMR (DMSO-d₆) δ: 5.00 (2H, s), 6.59-6.63 (1H, m), 6.78 (1H, dd,J=8.1, 1.2 Hz), 6.96-7.01 (1H, m), 7.25 (1H, dd, J=7.8, 1.2 Hz), 7.44(2H, d, J=8.8 Hz), 7.91 (2H, d, J=8.8 Hz), 10.04 (1H, s), 10.91 (1H, s).

MS (FAB): 290 (M+H)⁺.

Referential Example 404N-((1R,2S,5S)-2-Azido-5-{[ethyl(methyl)amino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained by treating the compound obtained inReferential Example 323 with hydrochloric acid, performing deprotectionand then condensing this product with the compound obtained inReferential Example 10 in a similar manner to the process described inReferential Example 252.

¹H-NMR (CDCl₃) δ: 1.08 (½ of 3H, t, J=7.2 Hz), 1.14 (½ of 3H, t, J=7.2Hz), 1.70-1.90 (4H, m), 2.10-2.25 (2H, m), 2.52 (3H, s), 2.78-3.00 (8H,m), 3.25-3.45 (2H, m), 3.69 (1H, d, J=13.4 Hz), 3.73 (1H, d, J=13.4 Hz),3.87-3.95 (1H, m), 4.55-4.62 (1H, m), 7.26 (1H, d, J=7.6 Hz).

Referential Example 405 Phenyl 2-(4-chlorophenyl)-1-hydrazinecarboxylate

(4-Chlorophenyl)hydrazine hydrochloride (3.00 g) was dissolved intetrahydrofuran (50 ml), diethyl ether (50 ml) and a saturated aqueoussolution of sodium hydrogencarbonate. An organic layer was separated,dried over anhydrous sodium sulfate and then concentrated, giving(4-chlorophenyl)hydrazine as a brown solid. This product was dissolvedin benzene (15 ml), and the solution was heated under reflux, to which asolution of diphenyl carbonate (5.22 g) in benzene (8.0 ml) was addeddropwise over at least 30 minutes. After refluxing for 19 hours, thereaction mixture was allowed to cool and concentrated. Benzene (15 ml)was then added to the residue. The mixture was subjected to ultrasonictreatment, giving a suspension. After hexane (50 ml) was added to thesuspension, and the mixture was stirred for 30 minutes, insoluble matterwas collected by filtration and dried to obtain the title compound (1.05g).

¹H-NMR (CDCl₃) δ: 5.86 (1H, br.s), 6.83-6.92 (3H, m), 7.17 (1H, br.s),7.20-7.32 (4H, m), 7.37 (2H, t, J=7.7 Hz).

MS (ESI) m/z: 263 (M+H)⁺.

Referential Example 406 Lithium5-tert-butoxycarbonyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxylate

The title compound was obtained from the compound obtained inReferential Example 33 in a similar manner to the process described inReferential Example 10.

¹H-NMR (DMSO-d₆) δ: 1.46 (9H, s), 4.30-4.70 (4H, m).

Referential Example 407 Benzyl 1-hydroxycyclopropanecarboxylate

Triethylamine (1.0 ml) and benzyl bromide (650 μl) were added to asolution of 1-hydroxycyclopropanecarboxylic acid (409 mg) intetrahydrofuran (3.0 ml), and the mixture was stirred at roomtemperature for 23 hours. Methylene chloride and 1N hydrochloric acidwere added to the reaction mixture to separate the mixture into twolayers. An organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and saturated aqueous solution of sodiumchloride and then dried over anhydrous sodium sulfate. A crude productwas purified by column chromatography on silica gel (hexane:ethylacetate=4:1) to obtain the title compound (607 mg).

¹H-NMR (CDCl₃) δ: 1.16 (2H, dd, J=7.9, 4.9 Hz), 1.32 (2H, dd, J=7.9, 4.9Hz), 3.09 (0.5H, s), 3.11 (0.5H, s), 5.17 (2H, s), 7.30-7.39 (5H, m).

MS (FAB) m/z: 192 (M+H)⁺.

Referential Example 408 Benzyl 1-methoxycyclopropanecarboxylate

60% Sodium hydride in oil (345 mg) and methyl iodide (900 μl) were addedto a solution of the compound (600 mg) obtained in Referential Example407 in tetrahydrofuran (5.0 ml), and the mixture was heated under refluxfor 28 hours. Ethyl acetate and a saturated aqueous solution of ammoniumchloride were added to the reaction mixture to separate the mixture intotwo layers. An organic layer was washed with saturated aqueous solutionof sodium chloride and then dried over anhydrous sodium sulfate. A crudeproduct was purified by column chromatography on silica gel(hexane:ethyl acetate=10:1) to obtain the title compound (340 mg).

¹H-NMR (CDCl₃) δ: 1.16 (2H, dd, J=7.9, 4.8 Hz), 1.31 (2H, dd, J=7.9, 4.8Hz), 3.42 (3H, s), 5.18 (2H, s), 7.30-7.39 (5H, m).

MS (FAB) m/z: 207 (M+H)⁺.

Referential Example 409 1-Methoxycyclopropanecarboxylic acid

The title compound was obtained from the compound obtained inReferential Example 408 in a similar manner to the process described inReferential Example 152.

¹H-NMR (CDCl₃) δ: 1.23 (2H, dd, J=8.0, 4.9 Hz), 1.38 (2H, dd, J=8.0, 4.9Hz), 3.45 (3H, s), 8.80-9.00 (1H, br).

Referential Example 410 tert-Butyl(3R,4S)-4-({7-chloroisoquinolin-3-yl}carbonyl)amino}-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 220 in a similar manner to the process described inReferential Example 214.

¹H-NMR (CDCl₃) δ: 1.46 (9H, br s), 1.62-1.80 (1H, m), 2.04-2.22 (1H, m),2.95-3.32 (1H, m), 3.38-3.53 (1H, m), 3.46 (3H, s), 3.84-3.95 (1H, m),4.02-4.27 (3H, m), 4.30-4.65 (2H, m), 4.87-4.98 (0.5H, br), 5.32-5.43(0.5H, br), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.94 (1H, d, J=8.8 Hz), 8.02(1H, s), 8.55-8.66 (0.7H, br), 8.58 (1H, s), 8.73-8.85 (0.3H, br), 9.14(1H, br s).

MS (ESI) m/z: 477 (M+H)⁺.

Referential Example 411 tert-Butyl(3R,4S)-4-{[2-(4-chloro-3-fluoroanilino)-2-oxoacetyl]amino}-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained by condensing the compound obtained inReferential Example 220 with the compound obtained in ReferentialExample 337 in a similar manner to the process described in ReferentialExample 214.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.60-1.75 (1H, m), 1.92-2.08 (1H, m),2.68-2.80 (0.5H, m), 2.88-3.03 (0.5H, m), 3.06-3.24 (0.5H, m), 3.27-3.36(0.5H, m), 3.45 (3H, s), 3.90-4.22 (5H, m), 4.56-4.71 (1H, m), 4.80-4.92(0.3H, br), 5.44-5.54 (0.7H, br), 7.24 (1H, d, J=12.9 Hz), 7.35 (1H, t,J=8.3 Hz), 7.72 (1H, dd, J=8.3, 2.3 Hz), 8.20-8.42 (1H, br), 9.18-9.28(1H, br).

MS (ESI) m/z: 487 (M+H)⁺.

Referential Example 412 tert-Butyl(3R,4S)-4-({2-[(5-chloro-2-thienyl)amino]-2-oxoacetyl}amino)-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 220 and the lithium salt of a carboxylic acidobtained by hydrolyzing the compound obtained in Referential Example 356in a similar manner to the process described in Referential Example 214.

¹H-NMR (CDCl₃): 1.45 (9H, s), 1.55-1.75 (1H, br), 1.90-2.10 (1H, br),2.68-2.80 (0.7H, m), 2.90-3.03 (0.3H, br), 3.07-3.22 (0.3H, br),3.25-3.35 (0.7H, br), 3.45 (3H, s), 3.83-4.22 (5H, m), 4.55-4.70 (1H,br), 4.80-4.90 (0.2H, br), 5.07-5.14 (0.2H, br), 5.44-5.55 (0.6H, br),6.58-6.64 (1H, br), 6.73 (1H, d, J=3.9 Hz), 8.05-8.27 (1H, br),9.65-9.88 (1H, br).

MS (FAB) m/z: 475 (M+H)⁺.

Referential Example 413 Ethyl5-methyl-5H-pyrrolo[3,4-d]thiazolo-2-carboxylate

1) Ethyl 2-thioxoacetate (26.75 g) was added to a solution of3-bromo-2-butanone (26.36 g) in ethanol (250 ml), and the mixture washeated under reflux for 14 hours. After cooling the reaction mixture, itwas concentrated, and ethyl acetate and saturated aqueous solution ofsodium chloride were added to separate the mixture into two layers. Anorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=6:1) to obtain ethyl4,5-dimethylthiazole-2-carboxylate (19.53 g).

¹H-NMR (CDCl₃) δ: 1.42 (3H, t, J=7.1 Hz), 2.42 (3H, s), 2.44 (3H, s),4.45 (2H, q, J=7.1 Hz).

2) N-Bromosuccinimide (62.42 g) and 2,2′-azobisisobutyronitrile (227 mg)were added to a solution of the above-described product (19.53 g) in1,2-dichloroethane (500 ml), and the mixture was refluxed for 42 hours.After cooling the reaction mixture, water and methylene chloride wereadded to separate the mixture into two layers. An organic layer waswashed with saturated aqueous solution of sodium chloride and thenconcentrated under reduced pressure to obtain a crude product (40.54 g)as a dark brown oil. Triethylamine (8.0 ml) and a 2 M tetrahydrofuransolution (11.0 ml) of methylamine were added to the crude product (8.41g), and the mixture was stirred at room temperature for 3 days. Afterthe reaction mixture was concentrated under reduced pressure, methylenechloride and saturated aqueous solution of sodium chloride were added tothe residue to separate the mixture into two layers. An organic layerwas washed with saturated aqueous solution of sodium chloride and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=3:1) to obtain the title compound(270 mg).

¹H-NMR (CDCl₃) δ: 1.45 (3H, t, J=7.1 Hz), 3.91 (3H, s), 4.48 (2H, q,J=7.1 Hz), 6.73 (1H, d, J=1.7 Hz), 7.30 (1H, d, J=1.7 Hz).

MS (ESI) m/z: 211 (M+H)⁺.

Referential Example 414 Ethyl 6-chloro-4-oxo-4H-chromene-2-carboxylate

About 60% sodium hydride in oil (1.68 g) was added to ethanol (10 ml)under purging with argon, and the mixture was stirred at roomtemperature for 10 minutes. After diethyl oxalate (3.36 ml) was added,an ethanol solution (20 ml) of 5′-chloro-2′-hydroxyacetophenone (2.82 g)was added dropwise. Ethanol (40 ml) was additionally added, and themixture was refluxed for 1.5 hours and stirred at 50° C. for 14 hours.Concentrated sulfuric acid (1.5 ml) and ethanol (10 ml) were added tothe reaction mixture, and the resultant mixture was refluxed for 4hours. After cooling, the solvent was decreased to a half byconcentration under reduced pressure. Toluene and a 1N aqueous solution(15 ml) of sodium hydroxide were added to the concentrated the reactionmixture. Extraction was conducted with ethyl acetate, and the resultantorganic layer was washed with saturated aqueous solution of sodiumchloride and then dried over anhydrous sodium sulfate. After the solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=7:1), theresultant solids were washed with hexane to obtain the title compound(1.20 g).

¹H-NMR (CDCl₃) δ: 1.44 (3H, t, J=7.1 Hz), 4.47 (2H, q, J=7.1 Hz), 7.12(1H, s), 7.58 (1H, d, J=9.0 Hz), 7.69 (1H, dd, J=9.0, 2.7 Hz), 8.16 (1H,d, J=2.7 Hz).

MS (ESI) m/z: 293 (M+MeCN+H)⁺.

Referential Example 415 6-Chloro-4-oxo-4H-chromene-2-carboxylic acid

The title compound was obtained from the compound obtained inReferential Example 414 in a similar manner to the process described inReferential Example 359.

¹H-NMR (CDCl₃) δ: 7.12 (1H, s), 7.60 (1H, d, J=8.8 Hz), 7.69 (1H, dd,J=8.8, 2.7 Hz), 8.15 (1H, d, J=2.7 Hz).

MS (FAB) m/z: 225 (M+H)⁺.

Referential Example 416 Ethyl(1S,3R,4S)-4-amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The title compound was obtained from the compound obtained inReferential Example 249 in a similar manner to the process described inReferential Example 90.

¹H-NMR (CDCl₃) δ: 1.20-1.80 (4H, m), 1.25 (3H, t, J=7.3 Hz), 1.46 (9H,s), 1.85-2.00 (1H, m), 2.10-2.20 (1H, m), 2.30-2.45 (1H, m), 2.90-3.00(1H, m), 3.84 (1H, br s), 4.12 (2H, q, J=7.3 Hz), 4.75 (1H, br s).

Referential Example 417 tert-Butyl(1R,2S,5S)-2-{[(6-chloro-4-oxo-4H-chromen-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

N,N-Dimethylformamide (0.02 ml) was added to a solution of the compound(213 mg) obtained in Referential Example 415 in thionyl chloride (2.0ml), and the mixture was refluxed for 15 minutes. The reaction mixturewas concentrated under reduced pressure, and the residue was dissolvedin tetrahydrofuran (4.0 ml). To the solution were added triethylamine(500 μl) and the compound (294 mg) obtained in Referential Example 144,and the mixture was stirred at room temperature for 15 minutes. Ethylacetate and a 10% aqueous solution of citric acid to separate thereaction mixture into two layers. An organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and saturatedaqueous solution of sodium chloride, dried over anhydrous sodium sulfateand then concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (methylenechloride:methanol=30:1) to obtain the title compound (230 mg).

¹H-NMR (CDCl₃) δ: 1.33-1.77 (3H, m), 1.50 (9H, s), 1.81-2.34 (3H, m),2.63-2.80 (1H, m), 2.95 (3H, s), 3.10 (3H, s), 3.90-4.04 (1H, br),4.18-4.31 (1H, br), 4.93-5.12 (1H, br), 7.13 (1H, s), 7.55 (1H, d, J=8.8Hz), 7.66 (1H, dd, J=8.8, 2.4 Hz), 8.14 (1H, d, J=2.4 Hz), 8.77-8.92(1H, br).

MS (ESI) m/z: 492 (M+H)⁺.

Referential Example 418 tert-Butyl(3R,4S)-4-{[(7-chlorocinnolin-3-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-ylcarbamate

The title compound was obtained from the compound obtained inReferential Example 220 and the lithium salt of a carboxylic acidobtained by hydrolyzing the ester described in Referential Example 297in a similar manner to the process described in Referential Example 214.

¹H-NMR (CDCl₃) δ: 1.38 (9H, s), 1.65-1.90 (1H, m), 1.90-2.15 (1H, m),2.80-3.00 (0.6H, m), 3.00-3.15 (0.4H, m), 3.20-3.50 (1H, m), 3.46 (3H,s), 3.80-4.70 (6H, m), 4.87 (0.4H, br s), 5.30 (0.6H, br s), 7.78 (1H,d, J=8.8 Hz), 7.97 (1H, d, J=8.8 Hz), 8.61 (1H, s), 8.62-8.90 (1H, br),8.73 (1H, s).

MS (ESI) m/z: 478 (M+H)⁺.

Referential Example 419 tert-Butyl(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained by condensing the compound obtained inReferential Example 144 with the compound obtained in ReferentialExample 266 in a similar manner to the process described in ReferentialExample 68.

¹H-NMR (CDCl₃) δ: 1.35-1.65 (1H, m), 1.45 (9H, s), 1.65-1.89 (2H, m),1.90-2.10 (3H, m), 2.56-2.74 (1H, br), 2.95 (3H, s), 3.06 (3H, s),3.94-4.01 (1H, m), 4.18-4.27 (1H, m), 4.70-4.90 (0.7H, br), 5.80-6.20(0.3H, br), 7.68 (1H, dd, J=8.9, 2.6 Hz), 7.83 (1H, br s), 8.14 (1H, brd, J=7.8 Hz), 8.30 (1H, s), 9.72 (1H, s).

MS (ESI) m/z: 468 (M+H)⁺.

Referential Example 420N¹-{(1S,2R,4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N²-(5-chloropyridin-2-yl)ethanediamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 419 in a similar manner to the process described inReferential Example 69.

¹H-NMR (DMSO-d₆) δ: 1.38-1.51 (1H, m), 1.65-1.85 (3H, m), 1.96-2.10 (2H,m), 2.81 (3H, s), 3.07 (3H, s), 3.23-3.33 (1H, m), 3.74 (1H, br s),3.84-3.92 (1H, m), 8.02 (1H, dd, J=9.0, 2.5 Hz), 8.07 (1H, d, J=9.0 Hz),8.34 (3H, br s), 8.46 (1H, d, J=2.5 Hz), 8.96 (1H, d, J=6.6 Hz), 10.34(1H, s).

MS (ESI) m/z: 368 (M+H)⁺.

Referential Example 421 tert-Butyl2-[({(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

The title compound was obtained by condensing the compound obtained inReferential Example 420 with5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 1.73-1.95 (3H, m), 1.95-2.06 (1H, m),2.08-2.20 (2H, m), 2.82 (3H, br s), 2.94 (3H, s), 3.03 (3H, s),3.60-3.80 (2H, m), 3.96-4.08 (1H, m), 4.44 (2H, br s), 4.66 (1H, br s),6.74 (1H, br s), 7.20-7.32 (1H, m), 7.66 (1H, dd, J=9.0, 2.4 Hz), 8.13(1H, d, J=9.0 Hz), 8.13-8.25 (1H, m), 8.28 (1H, d, J=2.4 Hz), 9.75 (1H,s).

MS (ESI) m/z: 633 (M+H)⁺.

Referential Example 422 2-Chloro-N-(4-fluorophenyl)acetamide

The title compound was obtained from p-fluoroaniline in a similar mannerto the process described in Referential Example 350.

¹H-NMR (CDCl₃) δ: 4.19 (2H, s), 7.05 (2H, t, J=8.6 Hz), 7.51 (2H, dd,J=9.1, 4.7 Hz), 8.19 (1H, br s).

Referential Example 423 SodiumS-[2-(4-fluoroanilino)-2-oxoethyl]thiosulfate

The title compound was obtained from the compound obtained inReferential Example 422 in a similar manner to the process described inReferential Example 351.

¹H-NMR (DMSO-d₆) δ: 3.72 (2H, s), 7.14 (2H, t, J=9.0 Hz), 7.56 (2H, dd,J=9.0, 5.1 Hz), 10.21 (1H, s).

Referential Example 424 tert-Butyl(1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-{[2-(4-fluoroanilino)-2-oxoethanethioyl]amino}cyclohexylcarbamate

The compound (1.1 g) obtained in Referential Example 144 and thecompound (1.2 g) obtained in Referential Example 423 were dissolved inN-methylmorpholine (20 ml), and the temperature of a bath was raisedfrom room temperature to 140° C. over 15 minutes to heat and stir themixture for 15 minutes at the same temperature. After allowing to cool,ice water was added to the reaction mixture to collect insoluble matterby filtration. This product was purified by column chromatography onsilica gel (methylene chloride:methanol=200:1→197:3) to obtain the titlecompound (1.43 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.70-2.10 (5H, m), 2.10-2.30 (1H, m),2.60-2.80 (1H, m), 2.96 (3H, s), 3.07 (3H, s), 4.30-4.50 (2H, m),4.65-4.85 (1H, m), 7.06 (2H, t, J=8.5 Hz), 7.50-7.70 (2H, m), 9.75-9.95(1H, m), 10.13 (1H, s).

MS (ESI) m/z: 467 (M+H)⁺.

Referential Example 425 2-Chloro-N-(5-fluoropyridin-2-yl)acetamide

The title compound was obtained from 2-amino-5-fluoropyridine in asimilar manner to the process described in Referential Example 352.

¹H-NMR (DMSO-d₆) δ: 4.35 (2H, s), 7.74-7.82 (1H, m), 8.10 (1H, dd,J=9.0, 4.2 Hz), 8.36 (1H, d, J=2.9 Hz), (1H, br s).

MS (ESI) m/z: 188 (M+H)⁺.

Referential Example 426 SodiumS-{2-[(5-fluoropyridin-2-yl)amino]-2-oxoethyl}thiosulfate

The title compound was obtained from the compound obtained inReferential Example 425 in a similar manner to the process described inReferential Example 353.

¹H-NMR (DMSO-d₆) δ: 3.75 (2H, s), 7.67-7.77 (1H, m), 8.07 (1H, dd,J=9.2, 4.2 Hz), 8.28 (1H, d, J=2.9 Hz), 10.48 (1H, s).

Referential Example 427 tert-Butyl(1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)amino]-2-oxoethanethioyl}amino)cyclohexylcarbamate

A solution of the compound (1.20 g) obtained in Referential Example 144in pyridine (70 ml) was heated to 120° C., and the compound (2.42 g)obtained in Referential Example 426 was added. After stirring themixture for 30 minutes, the reaction mixture was allowed to cool to roomtemperature, and the solvent was distilled off under reduced pressure.Methylene chloride (100 ml), a saturated aqueous solution (100 ml) ofsodium hydrogencarbonate and water (50 ml) were added to the resultantresidue to conduct liquid separation. A water layer was then extractedwith methylene chloride. Organic layers were combined and dried overanhydrous sodium sulfate, and the solvent was then distilled off underreduced pressure. The resultant residue was purified by columnchromatography on silica gel (hexane:tetrahydrofuran=1:1). After theresultant solids were slurried for 1 hour in isopropyl ether (40 ml),they were collected by filtration and dried to obtain the title compound(920 mg).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.70-2.10 (5H, m), 2.27 (1H, br s), 2.70(1H, br s), 2.96 (3H, s), 3.08 (3H, s), 4.34-4.44 (2H, m), 4.77 (1H, brs), 7.44-7.51 (1H, m), 8.18-8.27 (2H, m), 9.90 (1H, br s), 10.57 (1H,s).

MS (ESI) m/z: 468 (M+H)⁺.

Referential Example 428 tert-Butyl(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and the compound obtained in Referential Example353 in a similar manner to the process described in Referential Example427.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.65-2.35 (6H, m), 2.70 (1H, br s), 2.95(3H, s), 3.09 (3H, s), 4.30-4.60 (2H, m), 4.87 (½H, br s), 6.92 (½H, brs), 7.69 (1H, dd, J=8.9, 2.6 Hz), 7.95-8.20 (1H, br), 8.29 (1H, s), 9.67(½H, br s), 9.93 (½H, br s), 10.54 (1H, br s).

Referential Example 4292-Chloro-4,5,6,7-tetrahydrobenzothiazol-6-ylformamide

Ammonium acetate (18.58 g) and sodium cyanoborohydride (10.68 g) wereadded to a solution of 2-chloro-5-oxo-4,5,6,7-tetrahydrobenzo[d]thiazole(Helv. Cim. Acta., 1994, Vol. 77, p. 1256) (4.53 g) in methanol (200ml), and the mixture was heated under reflux. After 19 hours,hydrochloric acid was added to decompose excessive reagents before thereaction mixture was concentrated under reduced pressure. After theresidue was alkalified with a 1N aqueous solution of sodium hydroxide,methylene chloride was added to conduct liquid separation. The resultantorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas subjected to column chromatography on silica gel (methylenechloride:methanol=20:1), and the solvent was distilled off to obtain apale yellow oil (2.42 g). This oil was dissolved in methylene chloride(100 ml), and formic acid (530 μl),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.68 g),1-hydroxybenzotriazole (2.60 g) and N-methylmorpholine (3.88 g) wereadded to stir the mixture at room temperature. After 20 hours, methylenechloride and a saturated aqueous solution of sodium hydrogencarbonatewere added to the reaction mixture to conduct liquid separation. Theresultant organic layer was dried over anhydrous magnesium sulfate, thesolvent was then distilled off under reduced pressure, and the resultantresidue was purified by column chromatography on silica gel (methylenechloride:methanol=20:1) to obtain the title compound (2.21 g).

¹H-NMR (CDCl₃) δ: 1.93-2.11 (2H, m), 2.63-2.69 (1H, m), 2.83-2.89 (2H,m), 3.13 (1H, dd, J=16.2, 4.4 Hz), 4.46-4.48 (1H, m), 5.76 (1H, br s),8.17 (1H, s).

Referential Example 430 tert-ButylN-(2-chloro-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-methylcarbamate

A 1 M tetrahydrofuran solution (14.6 ml) of borane-tetrahydrofurancomplex was added to a solution of the compound (2.11 g) obtained inReferential Example 429 in tetrahydrofuran (50 ml), and the mixture washeated under reflux. After 15 hours, a 1 M tetrahydrofuran solution (6.0ml) of borane-tetrahydrofuran complex was additionally added to heat themixture under reflux. After 4 hours, ethanol (10 ml) and 1N hydrochloricacid (15 ml) were added to heat the mixture under reflux. After 3 hours,the reaction mixture was concentrated under reduced pressure. A 1Naqueous solution of sodium hydroxide and methylene chloride were addedto the residue to conduct liquid separation. The resultant organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue wasdissolved in methylene chloride (50 ml), and triethylamine (1.28 g) anddi-tert-butyl dicarbonate (2.21 g) were added to stir the mixture atroom temperature. After 30 minutes, methylene chloride and 1Nhydrochloric acid were added to conduct liquid separation. The resultantorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by column chromatography on silica gel (hexane:ethylacetate=2:1) to obtain the title compound (2.26 g).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.96-1.98 (2H, m), 2.80-2.96 (7H, m),4.40-4.50 (1H, m).

MS (FAB) m/z: 303 (M+H)⁺.

Referential Example 431 tert-ButylN-(2-[({(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-methylcarbamate

After a solution of the compound (1.0 g) obtained in Referential Example430 in diethyl ether (10 ml)-tetrahydrofuran (5 ml) was cooled −78° C.,a 1.6N pentane solution (3.1 ml) of tert-butyllithium was added, and themixture was stirred for 20 minutes. Carbon dioxide was then introducedfor 20 minutes. The reaction mixture was warmed to room temperature andconcentrated under reduced pressure, giving lithium6-[(tert-butoxycarbonyl)(methyl)amino]-4,5,6,7-tetrahydrobenzothiazole-2-carboxylate.

The lithium salt (350.2 mg) of the carboxylic acid obtained by theabove-described reaction, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (287.6 mg), 1-hydroxybenzotriazole (202.7 mg) andN-methylmorpholine (0.319 ml) were added to a solution of the compound(490.5 mg) obtained in Referential Example 420 in N,N-dimethylformamide(20 ml), and the mixture was stirred at room temperature for 4 days. Thesolvent was distilled off under reduced pressure, and water andmethylene chloride were added to the residue to conduct liquidseparation. The resultant organic layer was then successively washedwith a saturated aqueous solution of sodium hydrogencarbonate andsaturated aqueous solution of sodium chloride. The organic layer wasdried over anhydrous sodium sulfate, concentrated under reduced pressureand purified by column chromatography on silica gel (methylenechloride:methanol=40:1→20:1) to obtain the title compound (323.9 mg).

¹H-NMR (CDCl₃) δ: 1.48, 1.49 (total 9H, each s), 1.60-1.92 (4H, m),1.95-2.20 (6H, m), 2.78-3.10 (3H, m), 2.83 (3H, s), 2.95 (3H, s), 3.06,3.07 (total 3H, each s), 4.05-4.15 (1H, m), 4.20-4.60 (1H, m), 4.63-4.73(1H, m), 7.39 (1H, d, J=8.6 Hz), 7.68 (1H, dt, J=8.8, 2.6 Hz), 7.95-8.10(1H, m), 8.13-8.22 (1H, m), 8.30-8.35 (1H, m), 9.72 (1H, brs).

MS (ESI) m/z: 662 (M+H)⁺.

Referential Example 432N-{(1S,2R,4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-5-chloroindole-2-carboxamidehydrochloride

The title compound was obtained by deprotecting the compound obtained inReferential Example 310 in a similar manner to the process described inReferential Example 69.

¹H-NMR (DMSO-d₆) δ: 1.43-1.56 (0.5H, m), 1.72-1.97 (4.5H, m), 2.82 (3H,s), 3.06 (3H, s), 3.11-3.26 (1H, m), 3.75-3.84 (1H, m), 4.07-4.14 (1H,m), 4.22-4.41 (1H, m), 7.19 (1H, dd, J=2.0, 8.8 Hz), 7.29 (1H, d, J=2.0Hz), 7.45 (1H, d, J=8.8 Hz), 7.72 (1H, s), 8.07 (3H, br), 8.47 (1H, m),11.85 (1H, br).

Referential Example 433 Lithium2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate

Methyl chlorooxoacetate (78.7 ml) was added dropwise to a suspension of2-amino-5-chloropyridine (100 g) and sodium hydrogencarbonate (78.4 g)in tetrahydrofuran (2000 ml) at 0° C., and the mixture was stirred atroom temperature for 2 hours. After the reaction mixture was added to amixture of diethyl ether (2000 ml), ammonium chloride (62.4 g) and water(1000 ml), liquid separation was performed. The resultant water layerwas extracted with methylene chloride. Organic layers were combined anddried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure to obtain methyl2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (162 g). Water (450 ml) andlithium hydroxide (18.2 g) were added to a solution of this ester (160g) in tetrahydrofuran (1800 ml). After the mixture was stirred at roomtemperature for 2 hours, the solvent was distilled off under reducedpressure, and hexane (3000 ml) was added to the resultant residue tostir the mixture for 3 hours. Solids were collected by filtration anddried. Acetonitrile (1000 ml) was added to the solids (190 g), and themixture was stirred for 1 hour. Solids formed were collected byfiltration, washed with diethyl ether (500 ml) and then dried to obtainthe title compound (158 g).

¹H-NMR (DMSO-d₆) δ: 7.92 (1H, dd, J=9.1, 2.7 Hz), 8.13 (1H, dd, J=9.1,0.5 Hz), 8.36 (1H, dd, J=2.7, 0.5 Hz), 10.19 (1H, s).

Referential Example 434 tert-Butyl(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was obtained from the compound obtained inReferential Example 144 and the compound obtained in Referential Example433 in a similar manner to Referential Example 91.

¹H-NMR (CDCl₃) δ: 1.25-1.55 (1H, m), 1.45 (9H, s), 1.60-2.15 (5H, m),2.56-2.74 (1H, br), 2.95 (3H, s), 3.06 (3H, s), 3.90-4.01 (1H, m),4.18-4.27 (1H, m), 4.70-4.85 (0.7H, br), 5.70-6.00 (0.3H, br), 7.70 (1H,dd, J=8.8, 2.4 Hz), 7.75-8.00 (1H, br), 8.16 (1H, br d, J=8.8 Hz), 8.30(1H, d, J=2.4 Hz), 9.73 (1H, s).

MS (ESI) m/z: 468 (M+H)⁺.

Referential Example 435N¹-{(1S,2R,4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N²-(5-chloropyridin-2-yl)ethanediamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 434 in a similar manner to Referential Example 69.

¹H-NMR (DMSO-d₆) δ: 1.38-1.51 (1H, m), 1.65-1.85 (3H, m), 1.92-2.09 (2H,m), 2.80 (3H, s), 3.06 (3H, s), 3.20-3.32 (1H, m), 3.55-4.40 (2H, br),8.02 (1H, dd, J=9.1, 2.5 Hz), 8.07 (1H, d, J=9.1 Hz), 8.15-8.40 (3H,br), 8.45 (1H, d, J=2.5 Hz), 8.96 (1H, d, J=6.6 Hz), 10.33 (1H, s).

Example 1N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclopropyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

1-Hydroxybenzotriazole monohydrate (71 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg)were added to a solution with the compound (108 mg) obtained inReferential Example 59 and the compound (124 mg) obtained in ReferentialExample 10 dissolved in N,N-dimethylformamide (3 ml) at roomtemperature, and the mixture was stirred for 8 days. After concentratingthe reaction mixture under reduced pressure using a vacuum pump, water(50 ml) and a saturated aqueous solution (50 ml) of sodiumhydrogencarbonate were added to the residue to conduct extraction withmethylene chloride. The resultant organic layers were combined and driedover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure, and the residue was purified by preparative thin-layerchromatography on silica gel (methylene chloride:methanol=10:1). After1N hydrochloric acid, methylene chloride and methanol were added to thethus-obtained amorphous substance, the mixture was concentrated toobtain the title compound (72 mg).

¹H-NMR (DMSO-d₆) δ: 1.15-1.35 (2H, m), 2.88 (3H, s), 2.95-3.25 (4H, m),3.35-3.75 (2H, m), 4.32-4.45 (1H, m), 4.68 (1H, br, J=15.4 Hz), 7.08(1H, s), 7.17 (1H, dd, J=8.6, 2.1 Hz), 7.41 (1H, d, J=8.6 Hz), 7.70 (1H,s), 8.50 (1H, br, J=11.0 Hz), 8.56 (1H, br.s), 11.56 (1H, br, J=19.3Hz), 11.86 (1H, s).

MS (FAB) m/z: 430 (M+H)⁺.

Example 2N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclobutyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (136 mg) obtained in Referential Example 10,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (255 mg) and1-hydroxybenzotriazole monohydrate (90 mg) were added to a solution withthe compound (117 mg) obtained in Referential Example 60 dissolved inN,N-dimethylformamide (5 ml), and the mixture was stirred overnight atroom temperature. The solvent was then distilled off under reducedpressure using a vacuum pump, and methylene chloride and a saturatedaqueous solution of sodium hydrogencarbonate were added to the residueto conduct liquid separation. The resultant organic layer was washedwith saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:methylene chloride=7:93). After ethyl acetate and a1N ethanol solution of hydrochloric acid were added to the thus-obtainedcompound to acidify it, and the solvent was distilled off under reducedpressure. Ethyl acetate was added again, and precipitate formed wascollected by filtration and dried to obtain the title compound (56 mg).

¹H-NMR (DMSO-d₆) δ: 2.00-2.35 (4H, m), 2.88 (3H, m), 3.10 (2H, br.s),3.20-3.75 (3H, m), 4.20-4.85 (3H, m), 7.09 (1H, s), 7.16 (1H, d, J=8.8Hz), 7.38 (1H, d, J=8.8 Hz), 7.71 (1H, s), 8.63 (1H, d, J=8.3 Hz), 8.85(1H, d, J=8.6 Hz), 10.85-11.20 (1H, br), 11.81 (1H, s).

MS (FAB) m/z: 444 (M+H)⁺.

Example 3N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclopentyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

5-Chloroindole-2-carboxylic acid (80 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg),1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine (141 μl)were added to a solution with the compound (120 mg) obtained inReferential Example 62 dissolved in N,N-dimethylformamide (5 ml), andthe mixture was stirred at room temperature for 3 days. The solvent wasdistilled off under reduced pressure, and methylene chloride and asaturated aqueous solution of sodium hydrogencarbonate were added to theresidue to conduct liquid separation. The resultant organic layer waswashed with saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methylene chloride:methanol=93:7). After methylene chloride(5 ml) and a 1N ethanol solution (282 μl) of hydrochloric acid wereadded to the thus-obtained pale yellow solid, ethyl acetate was added,and precipitate formed was collected by filtration to obtain the titlecompound (109 mg).

¹H-NMR (DMSO-d₆) δ: 1.64-1.74 (4H, m), 1.98-2.02 (2H, m), 2.89 (3H, s),3.14 (2H, br.s), 3.47-3.65 (2H, m), 4.29-4.63 (4H, m), 7.10 (1H, d,J=1.5 Hz), 7.14 (1H, dd, J=8.5, 2.0 Hz), 7.38 (1H, d, J=8.5 Hz), 7.68(1H, d, J=2.0 Hz), 8.55 (1H, d, J=8.5 Hz), 8.91 (1H, d, J=8.5 Hz), 11.49(1H, br.s), 11.76 (1H, s).

MS (ESI) m/z: 458 (M+H)⁺.

Example 4N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)sulfonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (400 mg) obtained in Referential Example 67 was suspendedin methylene chloride (10 ml), triethylamine (0.514 ml) and(5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (Japanese PatentApplication Laid-Open No. 2000-119253) (319 mg) were added, and themixture was stirred at room temperature for 15 minutes. After water wasadded to the reaction mixture to conduct liquid separation, theresultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methylenechloride:methanol=100:3) to obtain a pale yellow foamy substance. Thissubstance was dissolved in tetrahydrofuran (3 ml), and methanol (2 ml)and a 1N aqueous solution (1.5 ml) of sodium hydroxide were added toheat the mixture under reflux for 2 hours. The reaction mixture wasconcentrated under reduced pressure, and methylene chloride and 1Nhydrochloric acid were added to the residue to conduct liquidseparation. After the resultant organic layer was dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methylene chloride:methanol=100:3). 1N Hydrochloric acid (1 ml) wasadded to the resultant product, and the mixture was concentrated underreduced pressure to obtain the title compound (108 mg).

¹H-NMR (DMSO-d₆) δ: 1.20-1.78 (8H, m), 2.94 (3H, s), 3.13 (2H, br.s),3.22-3.40 (1H, m), 3.44-3.70 (3H, m), 3.83-3.95 (1H, m), 4.20-4.70 (1H,m), 6.78 (1H, s), 7.18-7.30 (2H, m), 7.44 (1H, s), 7.69 (1H, br.s), 8.09(1H, br.s), 11.92 (1H, s).

MS (FAB) m/z: 508 (M+H)⁺.

Example 5N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

5-Chloroindole-2-carboxylic acid (109 mg), 1-hydroxybenzotriazolemonohydrate (9 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (321 mg) and triethylamine (0.232 ml) were added to asolution with the compound (300 mg) obtained in Referential Example 65dissolved in N,N-dimethylformamide (20 ml), and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure using a vacuum pump, and methylene chloride andwater were added to the residue to conduct liquid separation. Theresultant organic layer was dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methylenechloride:methanol=25:1) to obtain a colorless foamy substance. Thissubstance was suspended in 1N hydrochloric acid (1 ml), and thesuspension was concentrated under reduced pressure to obtain the titlecompound (203 mg).

¹H-NMR (DMSO-d₆) δ: 1.25-1.40 (2H, m), 1.46-1.81 (4H, m), 1.88-1.98 (2H,m), 2.89 (3H, s), 3.00-3.76 (5H, m), 3.86-3.97 (1H, m), 4.00-4.10 (1H,m), 4.25-4.72 (1H, m), 7.03 (1H, s), 7.12 (1H, dd, J=8.5, 1.2 Hz), 7.38(1H, d, J=8.5 Hz), 7.64 (1H, s), 8.28 (1H, d, J=8.5 Hz), 8.54 (1H, d,J=8.5 Hz), 11.70 (1H, s).

MS (FAB) m/z: 472 (M+H)⁺.

Example 6N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 67 and 5-chloroindole-2-carboxylic acid in a similarmanner to Example 5.

¹H-NMR (DMSO-d₆) δ: 1.35-1.70 (6H, m), 1.80-2.06 (2H, m), 2.89 (3H, s),3.00-3.27 (2H, m), 3.35-3.51 (1H, m), 3.57-3.82 (1H, m), 4.15-4.30 (2H,m), 4.32-4.48 (1H, m), 4.60-4.74 (1H, m), 7.15 (1H, s), 7.17 (1H, dd,J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.6 Hz), 7.70 (1H, d, J=2.0 Hz), 8.14(1H, br.s), 8.36-8.48 (1H, m), 11.51 (1H, br.s), 11.86 (1H, s).

MS (FAB) m/z: 472 (M+H)⁺.

Example 7N-{(1R*,2S*)-2-[(6-Chloro-2-naphthoyl)amino]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound (186 mg) was obtained by dissolving the compound (275mg) obtained in Referential Example 67, 6-chloronaphthalene-2-carboxylicacid (Eur. J. Chem. Chim. Ther., 1984, Vol. 19, pp. 205-214) (148 mg),triethylamine (0.298 ml) and 1-hydroxybenzotriazole monohydrate (11 mg)in N,N-dimethylformamide (20 ml) and causing1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (412 mg) toreact in a similar manner to Example 5.

¹H-NMR (DMSO-d₆) δ: 1.40-1.56 (2H, m), 1.57-1.77 (4H, m), 1.90-2.10 (2H,m), 2.90 (3H, s), 3.13 (2H, br.s), 3.28-3.74 (2H, m), 4.26 (2H, br.s),4.30-4.74 (2H, m), 7.59 (1H, d, J=8.6 Hz), 7.90 (1H, d, J=8.6 Hz), 7.98(1H, d, J=8.3 Hz), 8.03-8.11 (2H, m), 8.25-8.58 (3H, m), 11.52 (1H,br.s).

MS (FAB) m/z: 483 (M+H)⁺.

Example 8N-((1R*,2R*)-2-{[(6-Chloro-1-benzothiophen-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound (239 mg) was obtained by dissolving the compound (255mg) obtained in Referential Example 65,6-chlorobenzo[b]thiophene-2-carboxylic acid (Japanese Patent ApplicationLaid-Open No. 2000-119253) (141 mg), triethylamine (0.276 ml) and1-hydroxybenzotriazole monohydrate (10 mg) in N,N-dimethylformamide (20ml) and causing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (382 mg) to react in a similar manner to Example 5.

¹H-NMR (DMSO-d₆) δ: 1.20-1.98 (8H, m), 2.88 (3H, s), 3.00-3.72 (4H, m),3.84-4.09 (2H, m), 4.20-4.75 (2H, m), 7.41 (1H, dd, J=8.6, 1.7 Hz), 7.91(1H, d, J=8.6 Hz), 7.99 (1H, s), 8.12 (1H, s), 8.54-8.67 (2H, m), 11.53(1H, br.s).

MS (FAB) m/z: 489 (M+H)⁺.

Example 9N-((1R*,2R*)-2-{[(5-Fluoroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 65 and 5-fluoroindole-2-carboxylic acid in a similarmanner to Example 5.

¹H-NMR (DMSO-d₆) δ: 1.20-1.38 (2H, m), 1.40-1.57 (1H, m), 1.54-1.68 (1H,m), 1.71 (2H, d, J=7.3 Hz), 1.88 (2H, d, J=12.0 Hz), 2.86 (3H, s),2.95-3.24 (2H, m), 3.40 (1H, br.s), 3.63 (1H, br.s), 3.90 (1H, br.s),3.97-4.10 (1H, m), 4.20-4.44 (1H, m), 4.53-4.70 (1H, m), 6.98 (1H, dd,J=9.2, 2.3 Hz), 7.01 (1H, s), 7.31-7.39 (2H, m), 8.26 (1H, d, J=8.6 Hz),8.59 (1H, d, J=8.4 Hz), 11.21 (½H, br.s), 11.42 (½H, br.s), 11.60 (1H,s).

MS (ESI) m/z: 456 (M+H)⁺.

Example 10N-((1R*,2R*)-2-{[(5-Chloro-6-fluoroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 65 and the compound obtained in Referential Example23 in a similar manner to Example 5.

¹H-NMR (DMSO-d₆) δ: 1.20-1.40 (2H, m), 1.40-1.80 (4H, m), 1.80-2.00 (2H,m), 2.87 (3H, s), 3.01 (2H, br.s), 3.30-3.80 (2H, m), 3.81-3.97 (2H, m),4.20-4.80 (2H, m), 7.06 (1H, s), 7.28 (1H, d, J=10.0 Hz), 7.86 (1H, d,J=7.3 Hz), 8.32 (1H, d, J=8.5 Hz), 8.59 (1H, d, J=8.5 Hz), 11.77 (1H,s).

MS (FAB) m/z: 490 (M+H)⁺.

Example 11N-((1R*,2S*)-2-{[(5-Bromoindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 67 and 5-bromoindole-2-carboxylic acid in a similarmanner to Example 5.

¹H-NMR (DMSO-d₆) δ: 1.43 (2H, br.s), 1.61 (4H, br.s), 1.80-2.10 (2H, m),2.88 (3H, s), 3.00-3.26 (2H, m), 3.40 (1H, br.s), 3.65 (1H, br.s), 4.22(1H, br.s), 4.26 (1H, br.s), 4.41 (1H, br.s), 4.67 (1H, d, J=15.6 Hz),7.14 (1H, s), 7.28 (1H, d, J=8.7 Hz), 7.37 (1H, d, J=8.7 Hz), 7.84 (1H,s), 8.13 (1H, br.s), 8.33-8.52 (1H, m), 11.51 (1H, br.s), 11.86 (1H, s).

MS (ESI) m/z: 515 (M⁺).

Example 12N-((1R*,2S*)-2-{[(5-Ethynylindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

Triethylamine (6 ml), N,N-dimethylformamide (5 ml),trimethylsilylacetylene (0.250 ml) and palladium acetate (20 mg) wereadded to a tetrahydrofuran solution (2 ml) of the compound (300 mg)obtained in Example 11 and triphenylphosphine (70 mg) at roomtemperature. After stirring at 90° C. for 2 hours, the reaction mixturewas allowed to cool to room temperature, and methylene chloride (20 ml)and a saturated aqueous solution (30 ml) of sodium hydrogencarbonatewere added to conduct liquid separation. The resultant water layer wasextracted with methylene chloride (3×10 ml), the organic layers werecombined and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain residue. The resultantresidue was purified by preparative thin-layer chromatography on silicagel (methylene chloride:acetone:methanol=10:10:1) to obtain colorlesssolids. This product was dissolved in methanol (6 ml), potassiumcarbonate (120 mg) was added, and the mixture was stirred for 1 hour.Methylene chloride (20 ml) and water (20 ml) were added to the reactionmixture to conduct liquid separation. The resultant water layer wasextracted with methylene chloride (2×15 ml), the organic layers werecombined and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified bypreparative thin-layer chromatography on silica gel (methylenechloride:acetone:methanol=10:10:1) and dissolved inwater-methanol-methylene chloride. The resultant solution was thenconcentrated to obtain the title compound (72 mg).

¹H-NMR (CDCl₃) δ: 1.50-2.25 (8H, m), 2.53 (3H, s), 2.85 (2H, br.s), 2.93(2H, br.s), 3.01 (1H, s), 3.74 (1H, d, J=14.1 Hz), 3.77 (1H, d, J=14.1Hz), 4.21 (1H, br.s), 4.45 (1H, br.s), 6.91 (1H, s), 7.25-7.42 (2H, m),7.61 (1H, br.s), 7.80-7.97 (2H, m), 9.72 (1H, s).

MS (FAB) m/z: 462 (M+H)⁺.

Example 13N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example51 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.35-1.50 (2H, m), 1.50-1.75 (4H, m), 1.80-2.10 (2H,m), 2.70 (3H, br.s), 2.79 (3H, br.s), 4.10-4.70 (6H, m), 7.10-7.27 (2H,m), 7.41 (1H, d, J=8.8 Hz), 7.70 (1H, s), 8.12 (1H, d, J=6.8 Hz), 8.47(1H, d, J=7.6 Hz), 11.85 (1H, s).

MS (FAB) m/z: 487 (M+H)⁺.

Example 14N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example26 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.36-1.72 (6H, m), 1.90-2.10 (2H, m), 2.80-2.87 (2H,m), 3.93 (2H, t, J=5.6 Hz), 4.20-4.32 (2H, m), 4.81 (2H, s), 7.12 (1H,s), 7.15 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.67 (1H, d,J=1.7 Hz), 8.11 (1H, d, J=6.6 Hz), 8.36 (1H, d, J=8.3 Hz), 11.78 (1H,s).

MS (FAB) m/z: 459 (M+H)⁺.

Example 15N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example29 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.32-1.74 (6H, m), 1.82-2.10 (2H, m), 2.92 (3H, s),3.12-3.50 (3H, m), 3.69 (1H, br.s), 4.13-4.39 (3H, m), 4.51 (1H, br.s),7.10-7.19 (2H, m), 7.41 (1H, d, J=8.6 Hz), 7.68 (1H, s), 8.10 (1H,br.s), 8.40 (1H, br.s), 11.41 (1H, br.s), 11.87 (1H, s).

MS (FAB) m/z: 472 (M+H)⁺.

Example 16N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 69 and the compound obtained in Referential Example21 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.23-1.39 (2H, m), 1.40-1.81 (4H, m), 1.82-1.98 (2H,m), 2.60-3.00 (5H, m), 3.20-3.70 (2H, m), 3.87-3.96 (1H, m), 3.98-4.10(1H, m), 4.12-4.70 (2H, m), 7.04 (1H, d, J=1.5 Hz), 7.12 (1H, dd, J=8.8,2.0 Hz), 7.38 (1H, d, J=8.8 Hz), 7.65 (1H, d, J=2.0 Hz), 8.33 (1H, d,J=8.6 Hz), 8.72 (1H, d, J=8.6 Hz), 11.61 (1H, br.s), 11.72 (1H, s).

MS (FAB) m/z: 456 (M+H)⁺.

Example 17N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 71 with5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine-2-carboxylicacid (WO94/21599) and treating the formed product with hydrochloric acidto deprotect in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.42 (2H, br.s), 1.56-1.76 (4H, m), 1.98-2.11 (2H,m), 3.04 (2H, br.s), 3.32-3.45 (2H, m), 4.15 (3H, br.s), 4.26 (1H,br.s), 7.14 (1H, dd, J=8.8, 2.0 Hz), 7.23 (1H, s), 7.41 (1H, d, J=8.8Hz), 7.62 (1H, s), 7.77 (1H, s), 8.18-8.30 (2H, m), 9.42 (2H, br.s),11.92 (1H, s).

MS (FAB) m/z: 457 (M+H)⁺.

Example 18N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamidehydrochloride

The compound (171 mg) obtained in Example 17 was suspended in methylenechloride (10 ml), and triethylamine (0.104 ml) was added to stir themixture at room temperature for 10 minutes. After acetic acid (0.059 ml)was added to the reaction mixture, a 35% aqueous formaldehyde solution(0.070 ml) and sodium triacetoxyborohydride (118 mg) were added, and themixture was stirred at room temperature for 30 minutes. After a 1Naqueous solution (3 ml) of sodium hydroxide was added to the reactionmixture, water was added to conduct liquid separation. After theresultant organic layer was dried over anhydrous sodium sulfate, thesolvent was then distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel (methylenechloride:methanol=50:3) to obtain a colorless foamy substance. Thissubstance was suspended in 1N hydrochloric acid, and the suspension wasconcentrated under reduced pressure to obtain the title compound (85mg).

¹H-NMR (DMSO-d₆) δ: 1.40 (2H, br.s), 1.50-1.71 (4H, m), 1.97-2.05 (2H,m), 2.87 (3H, s), 2.98-3.20 (1H, m), 3.30-3.38 (2H, m), 3.54-3.70 (1H,m), 4.05-4.42 (4H, m), 7.14 (1H, d, J=8.6 Hz), 7.23 (1H, s), 7.40 (1H,d, J=8.6 Hz), 7.63 (1H, s), 7.77 (1H, s), 8.17-8.27 (2H, m), 10.83 (1H,br.s), 11.92 (1H, s).

MS (FAB) m/z: 471 (M+H)⁺.

Example 19N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-6-(dimethylamino)-4,5,6,7-tetrahydrobenzothiazole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example31 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.44 (2H, br.s), 1.52-1.68 (4H, m), 1.87-2.08 (3H,m), 2.30-2.40 (1H, m), 2.65-2.75 (1H, m), 2.77 (6H, s), 2.95-3.17 (2H,m), 3.30-3.70 (2H, m), 4.15-4.30 (2H, m), 7.10-7.20 (2H, m), 7.41 (1H,d, J=8.6 Hz), 7.69 (1H, s), 8.11 (1H, d, J=5.1 Hz), 8.34 (1H, d, J=8.1Hz), 10.95 (1H, br.s), 11.83 (1H, s).

MS (FAB) m/z: 500 (M+H)⁺.

Example 20N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-(pyridin-4-yl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

After n-butyllithium (1.60N hexane solution, 0.704 ml) was addeddropwise to a solution of the compound (204 mg) obtained in ReferentialExample 24 in tetrahydrofuran (3 ml) at −78° C., the mixture was stirredat 0° C. for 30 minutes. After the reaction mixture was cooled to −78°C. again, it was warmed to room temperature in 20 minutes while blowingcarbon dioxide, and the reaction mixture was concentrated under reducedpressure. The compound (400 mg) obtained in Referential Example 71,1-hydroxybenzotriazole monohydrate (254 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (360 mg) andisopropylamine (0.491 ml) were added to a solution of the resultantresidue in N,N-dimethylformamide (6 ml) at room temperature. Afterstirring for 3 days, the reaction mixture was concentrated under reducedpressure, and methylene chloride (30 ml), a saturated aqueous solution(100 ml) of sodium hydrogencarbonate and water (100 ml) were added tothe residue to conduct liquid separation. The resultant water layer wasextracted with methylene chloride (4×15 ml), the organic layers werecombined and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby column chromatography on silica gel (methylenechloride:methanol=20:1→10:1) and dissolved in 1N hydrochloricacid-methanol-methylene chloride. The resultant solution was thenconcentrated to obtain the title compound (245 mg).

¹H-NMR (DMSO-d₆) δ: 1.42 (2H, br.s), 1.60 (4H, br.s), 1.84-1.94 (1H, m),1.94-2.08 (1H, m), 2.97 (2H, br.s), 3.97-4.13 (2H, m), 4.19 (1H, br.s),4.27 (1H, br.s), 5.03 (2H, s), 7.13 (1H, br.s), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.32 (2H, br.s), 7.40 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=2.0 Hz),8.15 (1H, br, J=7.3 Hz), 8.31 (2H, d, J=5.9 Hz), 8.39 (1H, d, J=8.1 Hz),11.90 (1H, s), 14.03 (1H, br.s).

MS (ESI) m/z: 535 (M+H)⁺.

Example 21N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cycloheptyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 74 and the compound obtained in Referential Example10 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.51-1.55 (4H, m), 1.75-1.80 (6H, m), 2.88 (3H, s),3.12 (1H, br.s), 3.35-3.63 (4H, m), 4.10-4.13 (1H, m), 4.29-4.61 (2H,m), 7.06 (1H, s), 7.14 (1H, dd, J=8.8, 2.0 Hz), 7.39 (1H, d, J=8.8 Hz),7.67 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=8.3 Hz), 8.77 (1H, d, J=8.3 Hz),11.21-11.35 (1H, m), 11.71 (1H, s).

MS (ESI) m/z: 486 (M+H)⁺.

Example 22N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclooctyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 78 and the compound obtained in Referential Example10 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.61-2.06 (12H, m), 2.90 (3H, s), 3.08-3.17 (2H, m),3.43-3.45 (1H, br.s), 3.67 (1H, br.s), 4.43 (3H, br.s), 4.67 (1H, br.s),7.16-7.18 (2H, m), 7.42 (1H, d, J=8.8 Hz), 7.70 (1H, s), 8.24 (1H,br.s), 8.58 (1H, d, J=8.3 Hz), 11.43, 11.63 (1H, each br.s), 11.80 (1H,s).

MS (ESI) m/z: 500 (M+H)⁺.

Example 23N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclopentyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating a product obtained by thereaction of the compound obtained in Referential Example 63 with thecompound obtained in Referential Example 34 with hydrochloric acid in asimilar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.60-1.82 (4H, m), 1.91-2.15 (2H, m), 3.08 (2H, s),3.37-3.49 (2H, m), 4.28-4.56 (4H, m), 7.13 (1H, s), 7.15 (1H, d, J=8.8Hz), 7.40 (1H, d, J=8.8 Hz), 7.69 (1H, s), 8.61 (1H, d, J=8.3 Hz), 8.88(1H, d, J=8.3 Hz), 10.05 (2H, br.s), 11.82 (1H, s).

MS (FAB) m/z: 444 (M+H)⁺.

Example 24N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclopentyl)-5-isopropyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (30 mg) obtained in Example 23 was suspended in methylenechloride (20 ml), and triethylamine (260 μl) was added to stir themixture at room temperature for 15 minutes. Acetic acid (179 μl) andacetone (920 μl) were added to the reaction mixture, and the resultantmixture was stirred at room temperature for 2 minutes. Sodiumtriacetoxyborohydride (796 mg) was added to the reaction mixture to stirthem at room temperature for 5 hours. A 1N aqueous solution (10 ml) ofsodium hydroxide was added to the reaction mixture to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=100:3) to obtain a colorless foamy substance. Thisproduct was dissolved in methylene chloride, and a 1N ethanol solution(1 ml) of hydrochloric acid was added. The solution was concentratedunder reduced pressure to obtain the title compound (205 mg).

¹H-NMR (DMSO-d₆) δ: 1.27-1.39 (6H, m), 1.58-1.80 (4H, m), 1.95-2.10 (2H,m), 3.00-3.12 (1H, m), 3.25-3.45 (2H, m), 3.59-3.77 (2H, m), 4.25-4.39(1H, m), 4.40-4.55 (2H, m), 4.57-4.65 (1H, m), 7.10 (1H, s), 7.14 (1H,d, J=8.8 Hz), 7.38 (1H, d, J=8.8 Hz), 7.68 (1H, s), 8.56 (1H, d, J=8.8Hz), 8.90 (1H, d, J=8.8 Hz), 11.39 (1H, br.s), 11.76 (0.5H, s), 11.80(0.5H, s).

MS (FAB) m/z: 486 (M+H)⁺.

Example 25N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclopentyl)-5-ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (500 mg) obtained in Example 23 was dissolved inN,N-dimethylformamide (10 ml), and triethylamine (576 μl) and ethyliodide (329 μl) were added to stir the mixture overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure, and water was added to the residue to collect insoluble matterby filtration. This product was purified by column chromatography onsilica gel (methylene chloride:methanol=100:3) to obtain a pale brownfoamy substance. This substance was suspended in 1N hydrochloric acid,and the suspension was concentrated under reduced pressure to obtain thetitle compound (180 mg).

¹H-NMR (DMSO-d₆) δ: 1.32 (3H, t, J=7.1 Hz), 1.60-1.80 (4H, m), 1.96-2.10(2H, m), 3.20-3.39 (5H, m), 3.70-3.80 (1H, m), 4.26-4.58 (3H, m),4.68-4.79 (1H, m), 7.11 (1H, s), 7.15 (1H, dd, J=8.8, 2.0 Hz), 7.39 (1H,d, J=8.8 Hz), 7.69 (1H, d, J=1.5 Hz), 8.55 (1H, d, J=8.5 Hz), 8.92 (1H,d, J=8.5 Hz), 11.38 (1H, br.s), 11.70-11.80 (1H, m).

MS (FAB) m/z: 472 (M+H)⁺.

Example 26N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclopentyl)-5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 63 and the compound obtained in Referential Example39 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 0.81 (2H, br.s), 1.20-1.55 (5H, br), 1.55-1.80 (4H,m), 1.95-2.12 (2H, m), 3.05-3.40 (2H, br), 3.60-3.80 (2H, br), 4.25-4.80(4H, m), 7.10 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.39 (1H, d, J=8.8 Hz),7.69 (1H, s), 8.53 (1H, d, J=8.6 Hz), 8.85-8.95 (1H, m), 10.60-10.90(1H, br), 11.73 (1H, br.s).

MS (FAB) m/z: 498 (M+H)⁺.

Example 27N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-methoxycyclopentyl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride (Stereoisomer A and Stereoisomer B)

A mixture of the title compounds, i.e., Stereoisomer A and StereoisomerB was synthesized by condensing the compound (mixture of 4-positionstereoisomers) (268 mg) obtained in Referential Example 82 with thecompound obtained in Referential Example 10 in a similar manner toExample 2. The isomers were isolated by column chromatography on silicagel and then converted into hydrochlorides to obtain the title compounds[Stereoisomer A (75 mg) and Stereoisomer B (70 mg)].

Stereoisomer A:

¹H-NMR (DMSO-d₆) δ: 1.70-2.15 (4H, m), 2.90 (3H, s), 3.00-3.90 (8H, m),4.10-4.80 (4H, m), 7.08 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.38 (1H, d,J=8.8 Hz), 7.69 (1H, s), 8.56 (1H, d, J=8.8 Hz), 8.88 (1H, d, J=8.3 Hz),10.96 (1H, br.s), 11.75 (1H, br.s).

MS (FAB) m/z: 488 (M+H)⁺.

Stereoisomer B:

¹H-NMR (DMSO-d₆) δ: 1.60-2.10 (4H, m), 2.89 (3H, s), 3.00-3.70 (7H, m),3.70-3.90 (1H, m), 4.20-4.80 (4H, m), 7.05-7.20 (2H, m), 7.38 (1H, d,J=8.8 Hz), 7.68 (1H, s), 8.59 (1H, d, J=8.3 Hz), 8.90 (1H, d, J=8.5 Hz),11.26 (1H, br.s), 11.74 (1H, br.s).

MS (FAB) m/z: 488 (M+H)⁺.

Example 28N-[(1R*,2R*)-2{[(5-Chloroindol-2-yl)carbonyl]amino}-4-(hydroxymethyl)cyclopentyl]-5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride (Stereoisomer A)

1) Stereoisomers A and B ofN-((1R*,2R*)-4-[(benzyloxy)methyl]-2-{(5-chloroindol-2-yl)carbonyl}amino)cyclopentyl)-5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidewere obtained from the compound obtained in Referential Example 85 andthe compound obtained in Referential Example 42 in a similar manner toExample 2.

Stereoisomer A:

¹H-NMR (CDCl₃) δ: 1.05 (9H, s), 1.168, 1.171 (6H, each s), 1.53-1.61(1H, m), 1.76-1.88 (1H, m), 2.30-2.37 (2H, m), 2.78-2.79 (2H, m),2.87-2.90 (1H, m), 2.96-3.00 (1H, m), 3.37-3.47 (2H, m), 3.58 (2H, s),3.96 (1H, q, J=13.1 Hz), 4.41-4.45 (1H, m), 4.51-4.57 (2H, m), 6.88 (1H,d, J=1.5 Hz), 7.17 (1H, dd, J=8.8, 2.0 Hz), 7.23-7.43 (12H, m), 7.52(1H, d, J=7.6 Hz), 9.37 (1H, br.s).

Stereoisomer B:

¹H-NMR (CDCl₃) δ: 1.05 (9H, s), 1.17 (6H, s), 1.43-1.47 (1H, m),1.85-1.88 (1H, m), 2.09-2.14 (1H, m), 2.58-2.63 (1H, m), 2.78-2.79 (2H,m), 2.86-2.90 (1H, m), 2.96-3.00 (1H, m), 3.38-3.46 (2H, m), 3.59 (2H,s), 3.95 (1H, q, J=13.3 Hz), 4.15-4.20 (1H, m), 4.45-4.56 (3H, m), 6.74(1H, d, J=2.0 Hz), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.27-7.43 (12H, m),7.57 (1H, d, J=2.0 Hz), 9.48 (1H, br.s).

2) The above Stereoisomer A (288 mg) was suspended in methylene chloride(20 ml), and dimethyl sulfide (1.15 ml) and anhydrous aluminum chloride(350 mg) were added to stir the mixture at room temperature for 1 hour.A 1N aqueous solution (10 ml) of sodium hydroxide was added to thereaction mixture, and the mixture was extracted with methylene chloride.The resultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methylenechloride:methanol=9:1) to obtain 5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-N-[(1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-(hydroxymethyl)cyclopentyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(Stereoisomer A) (184 mg).

¹H-NMR (CDCl₃) δ: 1.04 (9H, s), 1.15 (6H, s), 1.54-1.62 (1H, m),1.73-1.81 (1H, m), 1.99-2.25 (2H, m), 2.34-2.38 (2H, m), 2.67-2.85 (3H,m), 2.92-2.97 (1H, m), 3.48-3.62 (4H, m), 3.93 (1H, q, J=15.6 Hz),4.20-4.28 (1H, m), 4.47-4.56 (1H, m), 6.89 (1H, s), 7.11-7.18 (1H, m),7.24-7.27 (1H, m), 7.32-7.43 (6H, m), 7.54 (1H, d, J=1.7 Hz), 7.63 (4H,dd, J=7.8, 1.5 Hz), 7.90-7.92 (2H, m), 10.13 (1H, br.s).

MS (FAB) m/z: 784 (M+H)⁺.

3) Stereoisomer A (180 mg) obtained in the step 2) described above wasdissolved in a 1N tetrahydrofuran solution (2 ml) of tetrabutylammoniumfluoride, and the solution was stirred overnight at room temperature.Methylene chloride, a 1N aqueous solution of sodium hydroxide and sodiumchloride were added to the reaction mixture to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=19:1). The thus-obtained powder was dissolved inmethanol, and a 1N ethanol solution (229 μl) of hydrochloric acid wasadded, to which ethyl acetate was added. The solvent was concentratedunder reduced pressure to obtain the title compound (63 mg).

¹H-NMR (DMSO-d₆) δ: 1.33-1.50 (8H, m), 1.70-1.91 (2H, m), 2.07-2.14 (1H,m), 2.23-2.24 (1H, m), 3.04-3.10 (1H, m), 3.27-3.44 (4H, m), 3.57-3.70(2H, m), 3.92-3.95 (1H, m), 4.29-4.72 (4H, m), 5.81 (1H, br.s), 7.11(1H, s), 7.15 (1H, dd, J=8.6, 2.0 Hz), 7.39 (1H, d, J=8.6 Hz), 7.68 (1H,d, J=2.0 Hz), 8.53-8.56 (1H, m), 8.83 (1H, d, J=8.3 Hz), 10.36 (1H,br.s), 11.75, 11.77 (1H, each s).

MS (ESI) m/z: 546 (M+H)⁺.

Example 29N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,7,8,10-tetrahydro-6H-pyrazolo[1,2-a]thiazolo[4,5-d]pyridazine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example44 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.35-1.50 (2H, m), 1.61 (4H, br.s), 1.80-2.00 (2H,m), 2.27 (2H, br.s), 2.80-4.80 (10H, m), 7.14 (1H, d, J=1.5 Hz), 7.17(1H, dd, J=8.5, 2.0 Hz), 7.41 (1H, d, J=8.5 Hz), 7.70 (1H, d, J=2.0 Hz),8.09 (1H, d, J=7.3 Hz), 8.44 (1H, br.s), 11.81 (1H, br.s).

MS (FAB) m/z: 499 (M+H)⁺.

Example 30N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,6,7,8,9,11-hexahydropyridazino[1,2-a]thiazolo[4,5-d]pyridazine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 46 and the compound obtained in Referential Example71 in a similar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.35-1.55 (2H, m), 1.55-2.10 (10H, m), 2.80-4.80(10H, m), 7.10-7.25 (2H, m), 7.42 (1H, d, J=8.8 Hz), 7.72 (1H, d, J=1.7Hz), 8.12 (1H, br.s), 8.41 (1H, br.s), 11.83 (1H, br.s).

MS (FAB) m/z: 513 (M+H)⁺.

Example 315-Chloro-N-{(1R*,2S*)-2-[(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-ylcarbonyl)amino]cyclohexyl}indole-2-carboxamidehydrochloride

The compound (171 mg) obtained in Referential Example 33 was dissolvedin diethyl ether (5 ml) in an argon atmosphere, and the solution wascooled to −78° C., to which n-butyllithium (1.60N hexane solution, 385μl) was added dropwise. After the reaction mixture was stirred for 10minutes at −78° C., and carbon dioxide was blown into the reactionmixture for 20 minutes, it was warmed to room temperature. After thereaction mixture was concentrated under reduced pressure, the residuewas dissolved in N,N-dimethylformamide (10 ml). To the solution, wereadded the compound (184 mg) obtained in Referential Example 71,1-hydroxybenzotriazole monohydrate (76 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215 mg).The resultant mixture was stirred for 3 days. The reaction mixture wasconcentrated, and methylene chloride and a saturated aqueous solution ofsodium hydrogencarbonate were added to the residue to separate anorganic layer. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressure.The resultant residue was purified by column chromatography on silicagel (methanol:methylene chloride=3:97). After an ethanol solution (5 ml)of hydrochloric acid was added to the thus-obtained product, the mixturewas stirred at room temperature for 1 hour, and the reaction mixture wasconcentrated. Ethyl acetate was added to the residue to solidify it. Theresultant powder was collected by filtration to obtain the titlecompound (31 mg).

¹H-NMR (DMSO-d₆) δ: 1.35-1.52 (2H, m), 1.55-1.80 (4H, m), 1.82-2.05 (2H,m), 4.22 (1H, br.s), 4.28 (1H, br.s), 4.38 (2H, s), 4.56 (2H, s),7.14-7.20 (2H, m), 7.42 (1H, d, J=8.6 Hz), 7.71 (1H, d, J=1.7 Hz), 8.10(1H, d, J=7.1 Hz), 8.45 (1H, d, J=7.8 Hz), 10.10-10.50 (2H, br), 11.83(1H, br.s).

MS (FAB) m/z: 444 (M+H)⁺.

Example 32 tert-Butyl2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

After the compound obtained in Referential Example 50 was hydrolyzedwith lithium hydroxide, it was reacted with the compound obtained inReferential Example 71 in a similar manner to Example 2 to obtain thetitle compound.

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 1.55-2.30 (8H, m), 4.23 (1H, br.s), 4.53(1H, br.s), 4.74-4.83 (4H, m), 6.99 (1H, d, J=1.5 Hz), 7.19 (1H, dd,J=8.8, 2.1 Hz), 7.34 (1H, d, J=8.8 Hz), 7.62 (1H, d, J=2.1 Hz), 8.11(1H, br.s), 8.48-8.53 (1H, br), 8.70-8.76 (1H, br), 9.60-9.70 (1H, br).

MS (ESI) m/z: 539 (M+H)⁺.

Example 33N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carboxamidehydrochloride

Trifluoroacetic acid (1 ml) was added to a solution of the compound(34.0 mg) obtained in Example 32 dissolved in methylene chloride (1 ml)at room temperature, and the mixture was stirred for 1 hour. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in methylene chloride (1 ml), to whichtriethylamine (17.6 μl), acetic acid (7.21 μl), 35% formalin (8.13 μl)and sodium triacetoxyborohydride (20.1 mg) were added at roomtemperature. The resultant mixture was stirred for 1 hour. Methylenechloride (10 ml) and saturated aqueous solution (10 ml) of sodiumhydrogencarbonate were added to the reaction mixture to separate anorganic layer. The organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(methanol:methylene chloride=7:93). A 1N ethanol solution ofhydrochloric acid and ethyl acetate were added to the product thusobtained to solidify it, and the resultant solids were collected byfiltration to obtain the title compound (8.0 mg).

¹H-NMR (DMSO-d₆) δ: 1.40-1.55 (2H, m), 1.55-1.75 (4H, m), 1.80-2.05 (2H,m), 2.98 (3H, br.s), 4.28 (2H, br.s), 4.65 (4H, br.s), 7.14-7.20 (2H,m), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.0 Hz), 8.17 (1H, d, J=6.9Hz), 8.65 (1H, d, J=8.3 Hz), 8.93 (1H, s), 11.73 (1H, br.s), 11.82 (1H,br.s).

MS (FAB) m/z: 453 (M+H)⁺.

Example 34N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating a product obtained by thereaction of the compound obtained in Referential Example 71 with thecompound obtained in Referential Example 34 with hydrochloric acid in asimilar manner to Example 2.

¹H-NMR (DMSO-d₆) δ: 1.39-1.52 (2H, m), 1.62 (4H, br.s), 1.86-2.09 (2H,m), 3.03 (2H, br.s), 3.40-3.47 (2H, m), 4.17-4.32 (2H, m), 4.44 (2H, s),7.15 (1H, s), 7.17 (1H, dd, J=8.6, 2.0 Hz), 7.41 (1H, d, J=8.6 Hz), 7.71(1H, s), 8.10-8.15 (1H, m), 8.40-8.47 (1H, m), 9.69 (2H, br.s), 11.85(1H, s).

MS (FAB) m/z: 458 (M+H)⁺.

Example 35N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-(2-methoxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 34and 2-methoxyethyl bromide in a similar manner to Example 25.

¹H-NMR (DMSO-d₆) δ: 1.44 (2H, br.s), 1.62 (4H, br.s), 1.85-2.10 (2H, m),2.76-3.21 (6H, m), 3.28 (3H, s), 3.64 (2H, br.s), 4.00-4.52 (4H, m),7.14 (1H, s), 7.17 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.70(1H, d, J=2.0 Hz), 8.08-8.20 (1H, m), 8.36-8.48 (1H, m), 11.84 (1H, s).

MS (FAB) m/z: 516 (M+H)⁺.

Example 36 Methyl2-[2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]acetatehydrochloride

The title compound was obtained from the compound obtained in Example 34and methyl bromoacetate in a similar manner to Example 25.

¹H-NMR (CDCl₃) δ: 1.52-1.98 (7H, m), 2.17 (1H, br.s), 2.87-3.10 (4H, m),3.49 (2H, s), 3.76 (3H, s), 3.93 (1H, d, J=15.4 Hz), 3.99 (1H, d, J=15.4Hz), 4.22 (1H, br.s), 4.45 (1H, br.s), 6.86 (1H, d, J=1.2 Hz), 7.18 (1H,dd, J=8.8, 2.0 Hz), 7.33 (1H, d, J=8.8 Hz), 7.58-7.63 (2H, m), 7.87 (1H,br.s), 9.88 (1H, br.s).

MS (FAB) m/z: 530 (M+H)⁺.

Example 37N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 34and acetone in a similar manner to Example 24.

¹H-NMR (DMSO-d₆) δ: 1.18-1.73 (8H, m), 1.81-2.10 (2H, m), 2.97-3.16 (1H,m), 3.20-3.41 (2H, m), 3.52-3.80 (2H, m), 4.19-4.31 (2H, m), 4.34-4.77(2H, m), 7.17 (1H, s), 7.18 (1H, dd, J=8.8, 2.0 Hz), 7.42 (1H, d, J=8.8Hz), 7.71 (1H, d, J=2.0 Hz), 8.15 (1H, br.s), 8.28-8.51 (1H, m), 11.31(1H, br.s), 11.86 (1H, s).

MS (FAB) m/z: 500 (M+H)⁺.

Example 38N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 34and tetrahydro-4H-pyran-4-one in a similar manner to Example 24.

¹H-NMR (DMSO-d₆) δ: 1.30-3.56 (19H, m), 3.70-4.01 (3H, m), 4.17-4.30(2H, m), 4.32-4.80 (1H, m), 7.15 (1H, s), 7.17 (1H, dd, J=8.6, 2.0 Hz),7.41 (1H, d, J=8.6 Hz), 7.71 (1H, d, J=2.0 Hz), 8.14 (1H, br.s), 8.39(1H, br.s), 11.84 (1H, s).

MS (FAB) m/z: 542 (M+H)⁺.

Example 39 tert-Butyl2-[2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]ethylcarbamate

The title compound was obtained from the compound obtained in Example 34and N-(tert-butoxycarbonyl)aminoacetoaldehyde (J. Org. Chem., 1988, Vol.53, p. 3457) in a similar manner to Example 24.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.54-1.98 (7H, m), 2.10-2.20 (1H, m),2.74 (2H, br.s), 2.92 (4H, br.s), 3.34 (2H, br.s), 3.84 (2H, br.s), 4.21(1H, br.s), 4.45 (1H, br.s), 6.86 (1H, s), 7.19 (1H, dd, J=8.8, 2.0 Hz),7.33 (1H, d, J=8.8 Hz), 7.57-7.63 (2H, m), 7.81 (1H, br.s), 9.66 (1H,br.s).

MS (FAB) m/z: 601 (M+H)⁺.

Example 405-(2-Aminoethyl)-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (450 mg) obtained in Example 39 was dissolved in methylenechloride (5 ml), and a saturated ethanol solution (30 ml) ofhydrochloric acid was added to stir the mixture at room temperature for1 minute. The reaction mixture was concentrated under reduced pressure,ethyl acetate was added to the residue, and solids deposited werecollected by filtration to obtain the title compound (367 mg).

¹H-NMR (DMSO-d₆) δ: 1.38-1.50 (2H, m), 1.61 (4H, br.s), 1.85-2.08 (2H,m), 3.00-4.62 (12H, m), 7.14 (1H, s), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.41(1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.0 Hz), 8.12 (1H, d, J=6.6 Hz),8.15-8.68 (4H, m), 11.85 (1H, s).

MS (FAB) m/z: 501 (M+H)⁺.

Example 41N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-{2-[(methylsulfonyl)amino]ethyl}-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (110 mg) obtained in Example 40 was dissolved in pyridine(3 ml), methanesulfonyl chloride (30 μl) was added, and the mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, and a 85:15 mixed solvent ofmethylene chloride and methanol, and water were added to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=100:3) to obtain a pale yellow foamy substance. Thisproduct was suspended in 1N hydrochloric acid (0.3 ml), and thesuspension was concentrated under reduced pressure to obtain the titlecompound (63 mg).

¹H-NMR (DMSO-d₆) δ: 1.38-1.50 (2H, m), 1.55-1.70 (4H, m), 1.86-2.05 (2H,m), 2.97 (3H, s), 3.02-3.25 (2H, m), 3.30-3.60 (5H, m), 3.78 (1H, br.s),4.18-4.30 (2H, m), 4.45-4.86 (2H, m), 7.14 (1H, s), 7.16 (1H, dd, J=8.8,2.0 Hz), 7.40 (1H, d, J=8.8 Hz), 7.41 (1H, br.s), 7.69 (1H, d, J=2.0Hz), 8.09 (1H, br.s), 8.43 (1H, br.s), 11.18 (1H, br.s), 11.82 (1H, s).

MS (FAB) m/z: 579 (M+H)⁺.

Example 42 Methyl2-[2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]ethylcarbamatehydrochloride

The compound (144 mg) obtained in Example 40 was dissolved in pyridine(3 ml), triethylamine (138 μl) was added, and the mixture was stirred atroom temperature for 5 minutes. A solution prepared by addingtriphosgene (49 mg) to tetrahydrofuran (1 ml) containing methanol (20μl) was added dropwise to this solution. After stirring for 1 hour, thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in a 9:1 mixed solvent of methylene chloride andmethanol. Water was added to the solution to conduct liquid separation.The resultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methylenechloride:methanol=100:3) to obtain a colorless foamy substance. Thisproduct was suspended in 1N hydrochloric acid (0.2 ml), and thesuspension was concentrated under reduced pressure to obtain the titlecompound (60 mg).

¹H-NMR (DMSO-d₆) δ: 1.38-1.50 (2H, m), 1.61 (4H, br.s), 1.85-2.04 (2H,m), 2.80-3.49 (8H, m), 3.52 (3H, s), 3.62-4.91 (4H, m), 7.14 (1H, s),7.16 (1H, dd, J=8.8, 2.0 Hz), 7.37 (1H, br.s), 7.40 (1H, d, J=8.8 Hz),7.70 (1H, s), 8.11 (1H, d, J=6.8 Hz), 8.40 (1H, br.s), 11.05 (1H, br.s),11.82 (1H, br.s).

MS (FAB) m/z: 559 (M+H)⁺.

Example 435-[2-(Acetylamino)ethyl]-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (90 mg) obtained in Example 40 was dissolved inN,N-dimethylformamide (3 ml), triethylamine (65 μl) and acetic anhydride(22 μl) were added, and the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure, and methylene chloride and a 0.3N aqueous solution of sodiumhydroxide were added to the residue to conduct liquid separation. Theresultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methylenechloride:methanol=100:3) to obtain a colorless foamy substance. Thisproduct was suspended in 1N hydrochloric acid (0.3 ml), and thesuspension was concentrated under reduced pressure to obtain the titlecompound (73 mg).

¹H-NMR (DMSO-d₆) δ: 1.39-1.52 (2H, m), 1.54-1.70 (4H, m), 1.83 (3H, s),1.84-2.06 (2H, m), 3.02-3.87 (8H, m), 4.16-4.32 (2H, m), 4.40-4.52 (1H,m), 4.78-4.88 (1H, m), 7.14 (1H, s), 7.16 (1H, d, J=8.6 Hz), 7.40 (1H,d, J=8.6 Hz), 7.70 (1H, s), 8.07-8.17 (1H, m), 8.22-8.30 (1H, m),8.38-8.52 (1H, m), 11.14 (1H, br.s), 11.83 (1H, s).

MS (FAB) m/z: 543 (M+H)⁺.

Example 44N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained in Example 34and 2-bromoethanol in a similar manner to Example 25.

¹H-NMR (DMSO-d₆) δ: 1.37-1.69 (6H, m), 1.86-2.03 (2H, m), 2.54-2.61 (2H,m), 2.75-2.86 (4H, m), 3.52-3.59 (2H, m), 3.75 (2H, s), 4.47 (1H, t,J=5.4 Hz), 7.12 (1H, s), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.40 (1H, d,J=8.8 Hz), 7.70 (1H, s), 8.05-8.13 (1H, m), 8.28-8.35 (1H, m), 11.78(1H, s).

MS (FAB) m/z: 502 (M+H)⁺.

Example 455-Butyl-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 34and n-bromobutane in a similar manner to Example 25.

¹H-NMR (DMSO-d₆) δ: 0.88 (3H, t, J=7.2 Hz), 1.20-1.70 (10H, m),1.87-2.05 (2H, m), 2.55-3.40 (8H, m), 4.16-4.30 (2H, m), 7.13 (1H, s),7.16 (1H, d, J=8.8 Hz), 7.40 (1H, d, J=8.8 Hz), 7.69 (1H, s), 8.05-8.14(1H, m), 8.35 (1H, br.s), 11.81 (1H, s).

MS (FAB) m/z: 514 (M+H)⁺.

Example 465-Acetyl-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (100 mg) obtained in Example 34 was dissolved inN,N-dimethylformamide (3 ml), triethylamine (84 μl) and acetic anhydride(29 μl) were added, and the mixture was stirred at room temperature for3 hours. The reaction mixture was concentrated under reduced pressure,and methylene chloride and 1N hydrochloric acid were added to theresidue to conduct liquid separation. The resultant organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (methylene chloride:methanol=100:3) to obtain the titlecompound (86 mg).

¹H-NMR (CDCl₃) δ: 1.52-1.85 (5H, m), 1.91 (2H, br.s), 2.10-2.28 (4H, m),2.77-3.00 (2H, m), 3.70-4.00 (2H, m), 4.19-4.38 (1H, m), 4.45 (1H,br.s), 4.68-4.99 (2H, m), 6.85 (1H, s), 7.17-7.22 (1H, m), 7.30-7.39(1H, m), 7.50-7.84 (3H, m), 9.72-10.05 (1H, m).

MS (FAB) m/z: 500 (M+H)⁺.

Example 47N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (100 mg) obtained in Example 34 was dissolved in pyridine(3 ml), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) wereadded, and the mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure, and methylenechloride and 1N hydrochloric acid were added to the residue to separatean organic layer. The resultant organic layer was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methylene chloride:methanol=100:1) to obtain the title compound (79mg).

¹H-NMR (CDCl₃) δ: 1.50-1.82 (5H, m), 1.90 (2H, br.s), 2.13 (1H, br.s),2.89 (3H, s), 2.91-2.98 (2H, m), 3.60-3.70 (2H, m), 4.30 (1H, br.s),4.44 (1H, br.s), 4.58 (2H, s), 6.87 (1H, s), 7.19 (1H, d, J=8.8 Hz),7.34 (1H, d, J=8.8 Hz), 7.61 (3H, br.s), 9.91 (1H, br.s).

MS (FAB) m/z: 536 (M+H)⁺.

Example 485-Methyl-N-((1R*,2S*)-2-{[(5-methylindol-2-yl)carbonyl]amino}cyclohexyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 67 and 5-methylindole-2-carboxylic acid in a similarmanner to Example 5.

¹H-NMR (DMSO-d₆) δ: 1.35-1.50 (2H, m), 1.50-1.80 (4H, m), 1.85-2.07 (2H,m), 2.36 (3H, s), 2.88 (3H, s), 3.12 (2H, br.s), 3.53 (2H, br.s),4.15-4.30 (2H, m), 4.30-4.80 (2H, br), 7.00 (1H, dd, J=8.4, 1.5 Hz),7.05 (1H, d, J=1.5 Hz), 7.30 (1H, d, J=8.4 Hz), 7.38 (1H, s), 8.00 (1H,d, J=7.3 Hz), 8.43 (1H, br.s), 11.45 (1H, br.s), 11.49 (1H, br.s).

MS (FAB) m/z: 452 (M+H)⁺.

Example 49 Ethyl(1R*,3S*,4R*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound (1.40 g) obtained in Referential Example 91 was suspendedin ethanol (8 ml), and a saturated ethanol solution (10 ml) ofhydrochloric acid was added at room temperature to stir the mixture for12 hours. The solvent was distilled off under reduced pressure to obtainethyl(1R*,3S*,4R*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylatehydrochloride (1.25 g).

The title compound was obtained from the above-described product and thecompound obtained in Referential Example 10 in a similar manner toExample 2.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 1.52-1.80 (2H, m), 2.03-2.37(4H, m), 2.53 (3H, s), 2.57-2.71 (1H, m), 3.73 and 3.78 (total 1H, eachd, J=14.4 Hz), 4.08-4.17 (1H, m), 4.18 (2H, q, J=7.2 Hz), 4.55-4.65 (1H,m), 6.85 (1H, br.s), 7.21 (1H, dd, J=8.8, 2.0 Hz), 7.33 (1H, d, J=8.8Hz), 7.48 (1H, d, J=7.6 Hz), 7.63 (1H, d, J=2.0 Hz), 7.98 (1H, d, J=7.6Hz), 9.30 (1H, s).

MS (ESI) m/z: 544 (M+H)⁺.

Example 50 Ethyl(1S,3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound (4.2 g) obtained in Referential Example 97 was suspended inethanol (25 ml), and a saturated ethanol solution (55 ml) ofhydrochloric acid was added at room temperature to stir the mixture for11 hours. The solvent was distilled off under reduced pressure to obtaincolorless solids (4.15 g).

This product (4.15 g) was dissolved in N,N-dimethylformamide (40 ml),and the compound (2.86 g) obtained in Referential Example 10,1-hydroxybenzotriazole monohydrate (1.72 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.15 g)were added to this solution at room temperature to stir the mixture for39 hours. The reaction mixture was concentrated under reduced pressure,and water was added to the residue to conduct extraction withchloroform. The resultant organic layer was washed with saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresultant residue was purified by column chromatography on silica gel(chloroform:methanol=100:1) to obtain the title compound (1.71 g).

[α]_(D) −94° (C=1.0, chloroform).

Example 51 Methyl(1R*,3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained by treating the compound obtained inReferential Example 107 with an ethanol solution of hydrochloric acidand then condensing this compound with the compound obtained inReferential Example 10 in a similar manner to Example 49.

¹H-NMR (DMSO-d₆) δ: 1.55-1.80 (3H, m), 1.80-2.20 (3H, m), 2.60-2.75 (1H,m), 2.92 (3H, s), 3.15-3.30 (1H, m), 3.30-3.50 (4H, m), 3.57 (3H, s),3.55-3.70 (1H, m), 4.20-4.30 (1H, m), 4.30-4.40 (1H, m), 7.02 (1H, s),7.17 (1H, dd, J=8.5, 2.0 Hz), 7.41 (1H, d, J=8.5 Hz), 7.71 (1H, s),8.20-8.35 (1H, m), 8.35-8.45 (1H, m), 11.82 (1H, br).

MS (FAB) m/z: 530 (M+H)⁺.

Example 52 Ethyl(1R*,3S*,4R*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained by treating the compound obtained inReferential Example 98 with a saturated ethanol solution of hydrochloricacid and then condensing it with 5-chloroindole-2-carboxylic acid in asimilar manner to Example 49.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 1.82-2.30 (6H, m), 2.49 (3H,s), 2.62-2.73 (1H, m), 3.74-3.85 (2H, m), 3.85-3.93 (2H, m), 3.71 (2H,s), 4.12-4.29 (3H, m), 4.49-4.59 (1H, m), 6.89 (1H, br.s), 7.21 (1H, dd,J=8.8, 2.0 Hz), 7.32 (1H, d, J=8.8 Hz), 7.33 (1H, br.s), 7.41 (1H,br.s), 7.62 (1H, br.s), 9.37 (1H, s).

MS (ESI) m/z: 544 (M+H)⁺.

Example 53 Methyl(1R*,3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained by treating the compound obtained inReferential Example 106 with a 4N dioxane solution of hydrochloric acidand then condensing it with 5-chloroindole-2-carboxylic acid in asimilar manner to Example 49.

¹H-NMR (DMSO-d₆) δ: 1.65-1.80 (3H, m), 1.80-2.10 (2H, m), 2.15-2.25 (1H,m), 2.55-2.70 (1H, m), 2.89 (3H, s), 3.05-3.20 (1H, m), 3.30-3.50 (4H,m), 3.55-3.65 (1H, m), 3.62 (3H, s), 4.20-4.30 (1H, m), 4.35-4.45 (1H,m), 7.19 (1H, dd, J=8.8, 1.2 Hz), 7.23 (1H, s), 7.43 (1H, d, J=8.8 Hz),7.73 (1H, s), 8.03 (1H, d, J=6.8 Hz), 8.73 (1H, d, J=8.5 Hz),11.15-11.38 (1H, br), 11.85 (1H, s).

MS (FAB) m/z: 530 (M+H)⁺.

Example 54 Methyl(1R,3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained by treating the compound obtained inReferential Example 112 a 4N dioxane solution of hydrochloric acid andthen condensing it with 5-chloroindole-2-carboxylic acid in a similarmanner to Example 49.

¹H-NMR (DMSO-d₆) δ: 1.67-1.76 (3H, m), 1.88-1.91 (1H, m), 2.01 (1H,br.s), 2.13-2.22 (1H, m), 2.52-2.67 (4H, m), 2.86 (2H, br.s), 3.04 (2H,br.s), 3.33-3.41 (1H, m), 3.61 (3H, s), 4.22-4.36 (3H, m), 7.17-7.22(2H, m), 7.42 (1H, d, J=8.8 Hz), 7.72 (1H, s), 8.00 (1H, d, J=6.9 Hz),8.68 (1H, d, J=8.6 Hz), 11.80 (1H, s).

MS (FAB) m/z: 530 (M+H)⁺.

Example 55N-((1R*,2S*,5S*)-5-(Aminocarbonyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained by treating the compound obtained inReferential Example 113 with a 4N dioxane solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example10.

¹H-NMR (CDCl₃) δ: 0.78-2.40 (7H, m), 2.53 (3H, s), 2.80-2.89 (1H, m),2.91-3.00 (1H, m), 3.68-3.76 (2H, m), 4.08-4.19 (1H, m), 4.54-4.65 (1H,m), 6.80 (1H, br.s), 7.21 (1H, dd, J=8.4, 1.6 Hz), 7.33 (1H, d, J=8.4Hz), 7.38-7.43 (1H, m), 7.49-7.55 (1H, m), 7.63 (1H, br.s), 9.14 (1H,br.s).

MS (ESI) m/z: 515 (M+H)⁺.

Example 56(1R*,3S*,4R*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid

The compound (916 mg) obtained in Example 49 was suspended in a mixedsolvent of ethanol (10 ml) and tetrahydrofuran (8 ml), and a 1N aqueoussolution (3.3 ml) of sodium hydroxide was added at room temperature tostir the mixture for 12 hours at the same temperature. After adding 1Nhydrochloric acid (3.3 ml), the solvent was distilled off under reducedpressure, and the residue was washed with water and diethyl ether toobtain the title compound (712 mg).

Example 57N-{(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

Triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg),1-hydroxybenzotriazole monohydrate (53 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg) wereadded to a chloroform suspension (10 ml) of the compound (168 mg)obtained in Example 56, and the mixture was stirred for 72 hours. Thesolvent was distilled off under reduced pressure, and water was added tothe residue to conduct extraction with chloroform. The resultant organiclayer was washed with saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the resultant residue was purified by columnchromatography on silica gel (methylene chloride:methanol=93:7). Thethus-obtained colorless solids (135 mg) were suspended in ethanol (5ml), to which 1N ethanol solution (0.5 ml) of hydrochloric acid wasadded. The mixture was stirred for 2 hours, and the solvent wasdistilled off to obtain the title compound (112 mg).

¹H-NMR (DMSO-d₆) δ: 1.42-2.07 (6H, m), 2.73-3.70 (10H, m), 2.88 (3H, s),2.97 (3H, s), 4.03-4.20 (1H, m), 4.51-4.67 (1H, m), 7.04 (1H, br.s),7.16 (1H, br, J=8.8 Hz), 7.41 (1H, d, J=8.8 Hz), 7.68 (1H, br.s),8.32-8.47 (2H, m), 10.76 (1H, br.s).

MS (ESI) m/z: 543 (M+H)⁺.

Example 58(1S,3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid

The compound (1.6 g) obtained in Example 50 was suspended in a mixedsolvent of ethanol (20 ml) and tetrahydrofuran (15 ml), and a 1N aqueoussolution (5.9 ml) of sodium hydroxide was added at room temperature tostir the mixture for 12 hours at the same temperature. After adding 1Nhydrochloric acid (5.9 ml), the solvent was distilled off under reducedpressure, and the residue was washed with water and diethyl ether toobtain the title compound (1.19 g).

m.p. 234-236° C.

[α]_(D) −57° (C=1.0, methanol).

Example 59N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(cyclopropylamino)carboyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 58and cyclopropylamine in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 0.32-0.40 (2H, m), 0.53-0.63 (2H, m), 1.50-2.10 (6H,m), 2.25-2.40 (1H, m), 2.45-2.70 (2H, m), 2.91 (3H, s), 3.05-3.80 (3H,m), 4.05-4.17 (1H, m), 4.30-4.55 (2H, m), 4.55-4.80 (1H, m), 7.03 (1H,d, J=1.5 Hz), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.68(1H, d, J=2.0 Hz), 7.86 (1H, br, J=3.4 Hz), 8.06 (1H, br.s), 8.40 (1H,br, J=7.6 Hz), 11.20-11.60 (1H, br), 11.79 (1H, s).

MS (FAB) m/z: 555 (M+H)⁺.

Example 60N-[(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(pyrrolidin-1-ylcarbonyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 58and pyrrolidine in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 1.45-2.10 (10H, m), 2.75-2.90 (2H, m), 2.90 (3H, s),3.10-3.70 (H, m), 4.05-4.20 (1H, m), 4.25-4.80 (3H, m), 7.05 (1H, s),7.17 (1H, d, J=8.7 Hz), 7.41 (1H, d, J=8.7 Hz), 7.69 (1H, s), 8.32 (1H,br, J=7.6 Hz), 8.38 (1H, br, J=7.1 Hz), 11.22 (1H, br.s), 11.78 (1H, s).

MS (FAB) m/z: 569 (M+H)⁺.

Example 61N-[(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(4-morpholinylcarbonyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 56and morpholine in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 1.40-2.05 (6H, m), 2.75-3.70 (18H, m), 4.02-4.17(1H, m), 4.55-4.69 (1H, m), 7.05 (1H, br.s), 7.17 (1H, br, J=8.8 Hz),7.41 (1H, d, J=8.8 Hz), 7.67 (1H, br.s), 8.35 (1H, d, J=7.6 Hz), 8.40(1H, d, J=7.6 Hz), 10.79 (1H, br.s).

MS (ESI) m/z: 585 (M+H)⁺.

Example 62N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(ethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (150 mg) obtained in Example 58 was dissolved inN,N-dimethylformamide (3 ml), to which N-ethylamine hydrochloride (119mg), 1-hydroxybenzotriazole monohydrate (79 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg) andtriethylamine (326 μl) were added, and the mixture was stirred at roomtemperature for 4 days. The solvent was distilled off under reducedpressure, and a saturated aqueous solution of sodium hydrogencarbonatewas added to the residue to conduct extraction with methylene chloride.The resultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultantresidue was purified by column chromatography on silica gel (methylenechloride:methanol=47:3). The thus-obtained solid was dissolved inmethylene chloride, to which 1N ethanol solution (171 μl) ofhydrochloric acid was added. The solvent was distilled off under reducedpressure, and methanol and diethyl ether were added to the residue tocollect precipitate formed by filtration, thereby obtaining the titlecompound (74 mg).

¹H-NMR (DMSO-d₆) δ: 0.99 (3H, t, J=7.2 Hz), 1.57-2.02 (6H, m), 2.33-2.38(1H, m), 2.92 (3H, s), 3.01-3.08 (2H, m), 3.17-3.20 (2H, s), 3.45-3.70(2H, m), 4.10-4.17 (1H, m), 4.40-4.69 (3H, m), 7.04 (1H, d, J=2.0 Hz),7.17 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.0Hz), 7.78-7.81 (1H, m), 8.08-8.12 (1H, m), 8.40 (1H, d, J=8.1 Hz), 11.23(1H, br.s), 11.79 (1H, br.s).

MS (FAB) m/z: 543 (M+H)⁺.

Example 63N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (900 mg) obtained in Example 58 was dissolved inN,N-dimethylformamide (50 ml), to which dimethylamine hydrochloride (304mg), 1-hydroxybenzotriazole monohydrate (262 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (369 mg) anddiisopropylethylamine (1.83 ml) were added, and the mixture was stirredat room temperature for 12 hours. The solvent was distilled off underreduced pressure, and a saturated aqueous solution of sodiumhydrogencarbonate was added to the residue to conduct extraction withmethylene chloride. The resultant organic layer was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the resultant residue was purified by column chromatography onsilica gel (methylene chloride:methanol=47:3). The thus-obtained whitesolids were dissolved in methylene chloride, to which 1N ethanolsolution (1.49 ml) of hydrochloric acid was added. The solvent wasdistilled off under reduced pressure, and methanol and diethyl etherwere added to the residue to collect precipitate formed by filtration,thereby obtaining the title compound (777 mg).

[α]_(D)=−53.90 (18° C., c=0.505, methanol).

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.70-1.85 (3H, m), 1.90-2.05 (2H,m), 2.80 (3H, s), 2.91 (3H, s), 2.95-3.10 (1H, m), 2.97 (3H, s),3.10-3.75 (4H, m), 4.05-4.15 (1H, m), 4.35-4.75 (3H, m), 7.05 (1H, s),7.16 (1H, dd, J=8.7, 2.1 Hz), 7.41 (1H, d, J=8.6 Hz), 7.67 (1H, s),8.30-8.45 (2H, m), 11.63 (1H, br), 11.78 (1H, s).

MS (FAB) m/z: 543 (M+H)⁺.

Example 64N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(2-methoxyethyl)(methyl)amino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 58in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 1.50-1.99 (6H, m), 2.80, 3.01 (3H, each s), 2.91(3H, s), 3.03 (1H, br.s), 3.16 (2H, s), 3.23 (3H, s), 3.35-3.67 (6H, m),4.09-4.16 (1H, m), 4.43-4.67 (3H, m), 7.04-7.06 (1H, m), 7.16 (1H, dd,J=8.8, 2.0 Hz), 7.42 (1H, d, J=8.8 Hz), 7.69 (1H, br.s), 8.29-8.41 (2H,m), 11.59 (1H, br.s), 11.80 (1H, br.s).

MS (FAB) m/z: 587 (M+H)⁺.

Example 65N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(2-hydroxyethyl)(methyl)amino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 58in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 1.50-1.55 (1H, m), 1.74-1.84 (3H, m), 1.94-1.97 (2H,m), 2.67, 3.02 (3H, each s), 2.91 (3H, s), 3.10-3.68 (9H, m), 4.11-4.13(1H, m), 4.43-4.66 (4H, m), 7.05 (1H, s), 7.16 (1H, dd, J=8.7, 2.0 Hz),7.41 (1H, d, J=8.7 Hz), 7.68 (1H, s), 8.34-8.40 (2H, m), 11.47 (1H,br.s), 11.79 (1H, s).

MS (FAB) m/z: 573 (M+H)⁺.

Example 66N-((1R,2S,5S)-5-(1-Azetidinylcarbonyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 58and azetidine hydrochloride in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 1.47-1.55 (1H, m), 1.65-1.82 (3H, m), 1.88-2.01 (2H,m), 2.16 (2H, quint., J=7.6 Hz), 3.17-3.67 (5H, m), 3.82 (2H, t, J=7.6Hz), 4.02-4.14 (3H, m), 4.43-4.67 (3H, m), 7.06 (1H, s), 7.17 (1H, dd,J=8.7, 1.7 Hz), 7.41 (1H, d, J=8.7 Hz), 7.69 (1H, br.s), 8.31 (1H, d,J=7.6 Hz), 8.38 (1H, d, J=7.6 Hz), 11.41 (1H, br.s), 11.80 (1H, s).

MS (FAB) m/z: 555 (M+H)⁺.

Example 67N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(3S)-3-fluoropyrrolidinyl]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinecarboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 58and (S)-3-fluoropyrrolidine (Synlett., 1995, p. 55) in a similar mannerto Example 57.

¹H-NMR (DMSO-d₆) δ: 1.23-3.77 (22H, m), 4.11-4.16 (1H, m), 4.58-4.51(1H, m), 5.23-5.42 (1H, m), 7.05 (1H, s), 7.16 (1H, d, J=8.3 Hz), 7.42(1H, d, J=8.3 Hz), 7.68 (1H, s), 8.34-8.37 (2H, m), 11.78 (1H, s).

MS (FAB) m/z: 587 (M+H)⁺.

Example 68 Lithium(1R*,3R*,4S*)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound (1.20 g) obtained in Example 51 was dissolved intetrahydrofuran (32 ml), and lithium hydroxide (60.8 mg) and water (4ml) were successively added under ice cooling to stir the mixture atroom temperature for 14 hours. The solvent was distilled off underreduced pressure to obtain the title compound (1.12 g).

¹H-NMR (DMSO-d₆) δ: 1.55-1.70 (2H, m), 1.70-2.05 (4H, m), 2.10-2.20 (1H,m), 2.25-2.40 (4H, m), 2.50-2.80 (4H, m), 3.45-3.65 (3H, m), 4.10-4.30(2H, m), 7.00-7.20 (2H, m), 7.50-7.65 (2H, m).

Example 69N-{(1R*,2S*,4S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 68and dimethylamine in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 1.40-1.60 (2H, m), 1.65-1.80 (2H, m), 1.95-2.10 (2H,m), 2.84 (3H, s), 2.90-3.05 (1H, m), 2.92 (3H, s), 3.06 (3H, s),3.15-3.75 (4H, m), 4.25-4.75 (4H, m), 7.02 (1H, d, J=1.5 Hz), 7.15 (1H,dd, J=8.8, 2.1 Hz), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.1 Hz), 8.05(1H, d, J=7.7 Hz), 8.63 (1H, d, J=7.7 Hz), 11.20 (1H, br), 11.79 (1H,s).

MS (FAB) m/z: 543 (M+H)⁺.

Example 70N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(3R)-3-hydroxypyrrolidinyl]carbonyl}cyclohexyl-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

1) The compound (1.18 g) obtained in Referential Example 58 wasdissolved in methanol (12 ml), 1N hydrochloric acid (240 μl) andpalladium hydroxide (221 mg) were added, and hydrogen was introduced toconduct catalytic reduction under normal pressure at room temperaturefor 4.5 hours. The catalyst was removed by filtration, and the filtratewas concentrated to solid under reduced pressure to obtain crude(3R)-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidine hydrochloride (984mg).

The thus-obtained product (249 mg), the product (295 mg) obtained inExample 58, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(126 mg) and 1-hydroxybenzotriazole monohydrate (87 mg) were dissolvedin N,N-dimethylformamide (10 ml). Diisopropylethylamine (450 μl) wasadded dropwise to the solution under ice cooling, and the mixture wasstirred at room temperature for 12 hours. The solvent was distilled offunder reduced pressure, methylene chloride and a saturated aqueoussolution of sodium hydrogencarbonate were added to the residue toconduct liquid separation. The resultant organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was subjected to column chromatography onsilica gel (methanol:methylene chloride=3:97) to obtainN-((1R,2S,5S)-5-[((3R)-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidinyl)carbonyl]-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide(248 mg).

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.50-1.60 (1H, m), 1.75-2.10 (5H, m),2.20-2.50 (2H, m), 2.54 (3H, d, J=2.8 Hz), 2.60-3.00 (5H, m), 3.30-3.80(6H, m), 4.10-4.20 (1H, m), 4.40-4.70 (2H, m), 6.85 (1H, s), 7.15-7.25(1H, m), 7.30-7.50 (8H, m), 7.60-7.70 (5H, m), 7.90-8.00 (1H, m), 9.38(1H, s).

MS (FAB) m/z: 823 (M+H)⁺.

2) The above product (240 mg) was dissolved in pyridine (10 ml), andhydrogen fluoride-pyridine complex (3.0 ml) was added dropwise under icecooling to stir the mixture at 0° C. for 4.5 hours. Ethyl acetate (80ml) was added to the reaction mixture under ice cooling to dilute it.The diluted reaction mixture was poured into ice. After sodiumhydrogencarbonate was added to this solution to alkalify it, liquidseparation was conducted. The resultant organic layer was dried overanhydrous sodium sulfate. The solvent was distilled under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:methylene chloride=1:19→1:9). The resultant crudepurified product was dissolved in methylene chloride and methanol, towhich 1N ethanol solution (225 μl) of hydrochloric acid was added to dryit once. Methanol and diethyl ether were added to the residue tosolidify it, thereby obtaining the title compound (114 mg).

¹H-NMR (DMSO-d₆) δ: 1.50-1.60 (1H, m), 1.70-2.10 (6H, m), 2.75-2.85 (1H,m), 2.92 (3H, s), 3.10-3.80 (8H, m), 4.10-5.10 (6H, m), 7.05 (1H, d,J=1.7 Hz), 7.16 (1H, dd, J=8.8, 1.7 Hz), 7.42 (1H, d, J=8.8 Hz), 7.68(1H, s), 8.30-8.45 (2H, m), 11.10-11.40 (1H, m), 11.78 (1H, s).

MS (FAB) m/z: 585 (M+H)⁺.

Example 71N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5,5-dimethoxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamideorN-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4,4-dimethoxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 118 and the compound obtained in Referential Example10 in a similar manner to Example 2.

¹H-NMR (CDCl₃) δ: 2.11-2.15 (1H, m), 2.21-2.25 (1H, m), 2.41-2.43 (1H,m), 2.46 (3H, s), 2.70-2.75 (1H, m), 2.81-2.88 (1H, m), 3.21 (3H, s),3.24 (3H, s), 3.49 (1H, s), 3.58 (1H, d, J=15.6 Hz), 3.71 (1H, d, J=15.6Hz), 3.87-3.93 (1H, m), 4.26-4.29 (1H, m), 6.85 (1H, d, J=2.0 Hz), 7.19(1H, dd, J=8.5, 2.0 Hz), 7.30 (1H, d, J=8.5 Hz), 7.62 (1H, s), 9.21 (1H,s).

Example 72N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-oxocyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamideorN-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-oxocyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (100 mg) obtained in Example 71 was dissolved in chloroform(2 ml), and trifluoroacetic acid (0.5 ml) and water (0.5 ml) were addedto stir the mixture at room temperature for 3.5 hours. A saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture to conduct extraction with ethyl acetate. The resultant organiclayer was washed with saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the resultant residue was purified by preparativethin-layer chromatography on silica gel (methylenechloride:methanol=19:1). The thus-obtained white solids were dissolvedin methanol (4 ml), to which a 1N ethanol solution (0.38 ml) ofhydrochloric acid was added. The solvent was distilled off under reducedpressure to obtain the title compound (35 mg).

¹H-NMR (DMSO-d₆) δ: 1.83-1.90 (1H, m), 2.08-2.10 (1H, m), 2.28-2.32 (1H,m), 2.50-2.59 (1H, m), 2.87 (3H, s), 2.96 (1H, t, J=13.0 Hz), 3.06-3.10(2H, m), 3.33-3.36 (3H, m), 4.02-4.04 (2H, m), 4.55-4.57 (2H, m), 7.03(1H, s), 7.15 (1H, d, J=8.8 Hz), 7.38 (1H, d, J=8.8 Hz), 7.69 (1H, s),8.43 (1H, d, J=8.8 Hz), 8.91 (1H, d, J=8.8 Hz), 11.75 (1H, s).

Example 73N-[(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(hydroxyimino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamideorN-[(1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-(hydroxyimino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (133 mg) obtained in Example 72 was dissolved in a mixedsolvent of pyridine (8 ml) and methanol (8 ml), and hydroxylaminehydrochloride (30 mg) was added to stir the mixture at room temperaturefor 3 days. The reaction mixture was concentrated, and water was addedto the residue to conduct extraction with ethyl acetate. The resultantorganic layer was washed with saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel (methylenechloride:methanol=97:3→17:3) to obtain the title compound (131 mg).

¹H-NMR (CDCl₃) δ: 1.43-1.86 (3H, m), 1.98-2.03 (1H, m), 2.26-2.30 (1H,m), 2.45 (3H, s), 2.47-2.51 (1H, m), 2.67-2.71 (1H, m), 2.78-2.86 (3H,m), 3.86-3.43 (2H, m), 4.16-4.24 (2H, m), 6.85 (1H, s), 7.13-7.16 (1H,m), 7.20-7.24 (1H, m), 7.46, 7.50 (total 1H, s), 7.56-7.64 (2H, m),9.59, 9.62 (total 1H, s).

Example 74N-((7R*,8S*)-8-{[(5-Chloroindol-2-yl)carbonyl]amino}-1,4-dioxaspiro[4.5]dec-7-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamideorN-((7R*,8S*)-7-{[(5-chloroindol-2-yl)carbonyl]amino}-1,4-dioxaspiro-[4.5]dec-8-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 120 and the compound obtained in Referential Example10 in a similar manner to Example 2.

¹H-NMR (CDCl₃) δ: 1.69-1.87 (6H, m), 2.14-2.17 (1H, m) 2.30-2.32 (1H,m), 2.47 (3H, s), 2.70-2.75 (1H, m), 2.81-2.89 (2H, m), 3.58 (1H, d,J=15.4 Hz), 3.72 (1H, d, J=15.4 Hz), 3.89-3.91 (1H, m), 3.99 (4H, s),4.37-4.40 (1H, m), 6.86 (1H, d, J=2.0 Hz), 7.19 (1H, dd, J=8.8, 2.0 Hz),7.30 (1H, d, J=8.8 Hz), 7.38 (1H, d, J=7.3 Hz), 7.62 (1H, d, J=2.0 Hz),9.15 (1H, s).

Example 75N-[(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(methoxyimino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamideorN-[(1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-(methoxyimino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

1) The compound (2.21 g) obtained in Referential Example 124 wasdissolved in methylene chloride (30 ml), and trifluoroacetic acid (6 ml)was added to stir the mixture at room temperature for 1.5 hours. Thereaction mixture was concentrated, dried with a vacuum pump and thendissolved in N,N-dimethylformamide (20 ml), to which5-chloroindole-2-carboxylic acid (500 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (593 mg),1-hydroxybenzotriazole monohydrate (473 mg) and N-methylmorpholine (2.8ml) were added. The mixture was stirred at room temperature for 10hours. Additionally, 5-chloroindole-2-carboxylic acid (242 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (237 mg) and1-hydroxybenzotriazole monohydrate (189 mg) were added to stir themixture for 4 hours. A saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture to conductextraction with ethyl acetate and with a mixed solvent of ethyl acetateand tetrahydrofuran. The resultant organic layers were washed withsaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the resultant residue was purified by column chromatography onsilica gel (methylene chloride:methanol=97:3→4:1) to obtainN-[(1R*,2S*)-2-amino-5-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxamide(368 mg) andN-[(1R*,2S*)-2-amino-4-(methoxyimino)-cyclohexyl]-5-chloroindole-2-carboxamide(300 mg).

2) The title compound (mixture of syn and anti isomers at themethoxyimino group) from one of the above-obtainedN-[(1R*,2S*)-2-amino-5-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxamideorN-[(1R*,2S*)-2-amino-4-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxamideand the compound obtained in Referential Example 10 in a similar mannerto Example 2.

¹H-NMR (CDCl₃) δ: 1.84-2.00 (3H, m), 2.26-2.56 (3H, m), 2.46 (3H, s),2.80-2.83 (4H, m), 3.57 (1H, q, J=15.4 Hz), 3.70 (1H, q, J=15.4 Hz),3.84, 3.85 (total 3H, s), 4.08-4.14 (1H, m), 4.26-4.30 (1H, m), 6.84(1H, s), 7.17 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=8.8 Hz), 7.46-7.48 (2H,m), 7.56 (1H, m), 9.42, 9.55 (total 1H, s).

Example 76N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-hydroxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide(Stereoisomer A) orN-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-hydroxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide(Stereoisomer A)

1)N-((1R*,2S*)-2-amino-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)-5-chloroindole-2-carboxamide(Stereoisomer A) andN-((1R*,2S*)-2-amino-5-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)-5-chloroindole-2-carboxamide(Stereoisomer A) were obtained by subjecting the ((1R*,2S*)-formobtained in Referential Example 125 to de(tert-butoxycarbonylation) inthe same manner as in the step 1) of Example 75 and reacting the formedproduct with 5-chloroindole-2-carboxylic acid.

2)N-((1R*,2S*)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(Stereoisomer A) orN-((1R*,2S*)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl-5)-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(Stereoisomer A) was obtained from the product obtained by the abovereaction and the compound obtained in Referential Example 10 in asimilar manner to Example 2.

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.55-1.61 (1H, m), 1.85-1.90 (1H, m),2.18-2.25 (1H, m), 2.46 (3H, s), 2.51 (2H, d, J=7.6 Hz), 2.72 (1H, m),3.56 (1H, s), 3.57 (1H, d, J=15.3 Hz), 3.72 (1H, d, J=15.3 Hz),3.71-3.81 (1H, m), 3.88-3.95 (1H, m), 6.78 (1H, s), 7.17 (1H, dd, J=2.0,8.8 Hz), 7.37-7.44 (7H, m), 7.59 (1H, s), 7.65-7.68 (6H, m), 9.30 (1H,s).

3) The title compound was obtained from the compound obtained by theabove-described reaction in the same manner as in the step 3) of Example28.

¹H-NMR (DMSO-d₆) δ: 1.25-1.30 (2H, m), 1.45-1.64 (2H, m), 1.86 (1H, d,J=9.0 Hz), 1.98-2.03 (1H, m), 2.33 (3H, s), 2.66-2.73 (2H, m), 2.75-2.79(2H, m), 3.54 (1H, d, J=15.6 Hz), 3.62 (1H, d, J=15.6 Hz), 3.96-4.02(2H, m), 4.78 (1H, d, J=4.2 Hz), 7.00 (1H, s), 7.14 (1H, dd, J=2.0, 8.8Hz), 7.38 (1H, d, J=8.8 Hz), 7.66 (1H, s), 8.20 (1H, d, J=7.8 Hz), 8.54(1H, d, J=7.8 Hz), 11.69 (1H, s).

Example 77N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-hydroxy-5-methylcyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(Stereoisomer A1) orN-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-hydroxy-4-methylcyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(Stereoisomer A2)

The title compounds were obtained by reacting the compound obtained inReferential Example 128 with the compound obtained in ReferentialExample 10 in a similar manner to Example 2.

Stereoisomer A1:

¹H-NMR (DMSO-d₆) δ: 1.24 (3H, s), 1.33-1.82 (4H, m), 2.34 (3H, s),2.67-3.64 (8H, m), 4.02-4.10 (2H, m), 4.67 (1H, br.s), 7.02 (1H, s),7.13 (1H, d, J=8.6 Hz), 7.38 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.0 Hz),8.21-8.26 (1H, br), 8.59 (1H, d, J=8.1 Hz), 11.73 (1H, br.s)

MS (FAB) m/z: 502 (M+H)⁺.

Stereoisomer A2:

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, s), 1.33-1.79 (4H, m), 2.33 (3H, s),2.65-3.63 (8H, m), 3.88-3.94 (1H, m), 4.20-4.25 (1H, m), 4.59 (1H, br),7.01 (1H, s), 7.13 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=8.6 Hz), 7.67 (1H,s), 8.29 (1H, br), 8.43 (1H, d, J=9.3 Hz), 11.67 (1H, br)

MS (FAB) m/z: 502 (M+H)⁺.

Example 78N-[(1R*,2R*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained by treating the compound obtained inReferential Example 129 with an ethanol solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example10 in a similar manner to Example 49.

¹H-NMR (DMSO-d₆) δ: 1.42-1.90 (5H, m), 2.07-2.26 (3H, m), 2.46 (3H, s),2.67-2.95 (4H, m), 3.55-3.80 (4H, m), 3.80-3.95 (1H, m), 4.13-4.25 (1H,m), 6.84 (1H, br.s), 7.17 (1H, dd, J=8.8, 2.0 Hz), 7.23-7.35 (2H, m),7.43 (1H, d, J=7.2 Hz), 7.58 (1H, br.s), 9.29 (1H, s).

MS (ESI) m/z: 502 (M+H)⁺.

Example 79N-[(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(methoxymethyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained by treating the compound obtained inReferential Example 135 with an ethanol solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example10 in a similar manner to Example 49.

¹H-NMR (CDCl₃) δ: 1.20-1.38 (1H, m), 1.50-1.67 (2H, m), 1.88-2.03 (2H,m), 2.03-2.14 (1H, m), 2.21-2.32 (1H, m), 2.53 (3H, s), 2.75-2.95 (2H,m), 3.20-3.35 (2H, m), 3.37 (3H, s), 3.73 (1H, d, J=16.0 Hz), 3.76 (1H,d, J=16.0 Hz), 4.04-4.13 (1H, m), 4.53-4.62 (1H, m), 6.85 (1H, d, J=2.0Hz), 7.19 (1H, dd, J=8.8, 2.0 Hz), 7.33 (1H, d, J=8.8 Hz), 7.54 (1H, d,J=7.2 Hz), 7.63 (1H, d, J=2.0 Hz), 8.07 (1H, d, J=5.6 Hz), 9.49 (1H,br.s).

Example 80N-((1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(methylsulfonyl)amino]methyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

1) The compound (437 mg) obtained in Referential Example 137 wasdissolved in ethanol (5 ml), and a 4N dioxane solution (5 ml) ofhydrochloric acid was added at room temperature to stir the mixture for13 hours. The solvent was distilled off, and the residue was dissolvedin N,N-dimethylformamide (10 ml), to which triethylamine (0.7 ml), thecompound (300 mg) obtained in Referential Example 10,1-hydroxybenzotriazole monohydrate (162 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg)were added. The mixture was stirred for 13 hours, and water was added tothe reaction mixture to conduct extraction with chloroform. Theresultant organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel (methylenechloride:methanol=97:3) to obtainN-((1R*,2S*,5S*)-5-(azidomethyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(330 mg).

¹H-NMR (DMSO-d₆) δ: 1.15-2.08 (7H, m), 2.33 (3H, s), 2.34-2.95 (6H, m),3.64 (2H, s), 4.05-4.17 (1H, m), 4.36-4.47 (1H, m), 7.02 (1H, s), 7.15(1H, dd, J=8.8, 2.0 Hz), 7.40 (1H, d, J=8.8 Hz), 7.67 (1H, d, J=2.0 Hz),8.02 (1H, d, J=7.6 Hz), 8.44 (1H, d, J=7.6 Hz), 11.8 (1H, s).

2) The compound (300 mg) obtained by the above reaction was dissolved inethanol (8 ml), and a catalytic amount of 10% palladium on carbon wasadded to stir the mixture at room temperature for 168 hours in ahydrogen atmosphere. Insoluble matter was filtered, and the solvent wasdistilled off. The thus-obtained crudeN-((1R*,2S*,5S*)-5-(aminomethyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(150 mg) was dissolved in chloroform (6 ml), and triethylamine (0.2 ml)and methanesulfonyl chloride (0.035 ml) were added to stir the mixturefor 13 hours. The solvent was distilled off under reduced pressure, andwater was added to the residue to conduct extraction with chloroform.The resultant organic layer was washed with a saturated aqueous solutionof sodium hydrogencarbonate and saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel (methylenechloride:methanol=24:1) to obtain the title compound (56 mg).

¹H-NMR (CDCl₃) δ: 1.18-1.34 (2H, m), 1.50-1.75 (4H, m), 1.90-2.30 (4H,m), 2.53 (3H, s), 2.78-2.90 (2H, m), 2.90-3.05 (6H, m), 3.20-3.30 (1H,m), 3.68-3.81 (2H, m), 3.98-4.08 (1H, m), 4.54-4.62 (1H, m), 6.10-6.19(1H, m), 6.86 (1H, s), 7.19 (1H, dd, J=8.8, 2.0 Hz), 7.35 (1H, d, J=8.8Hz), 7.52 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=2.0 Hz), 8.21 (1H, d, J=5.6Hz), 9.89 (1H, s).

MS (ESI) m/z: 579 (M+H)⁺.

Example 81N-{(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)methyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidetrifluoroacetate

The title compound was obtained from the amine obtained in the step 2)of Example 80 in a similar manner to Example 24.

¹H-NMR (DMSO-d₆) δ: 1.15-2.22 (7H, m), 2.40-2.65 (2H, m), 2.68-2.85 (6H,m), 2.92-3.08 (5H, m), 3.10-3.18 (2H, m), 4.08-4.20 (1H, m), 4.35-4.51(2H, m), 7.04 (1H, s), 7.14-7.20 (1H, m), 7.41 (1H, d, J=8.8 Hz), 7.67(1H, s), 8.25-8.42 (2H, m), 9.11 (1H, br.s), 9.89 (1H, s).

MS (ESI) m/z: 529 (M+H)⁺.

Example 82 tert-Butyl(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamate(Isomer B) and tert-butyl(3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamate(Isomer B)

The compound (Stereoisomer B) (1.79 g) obtained in Referential Example140 was dissolved in tetrahydrofuran (36 ml), and 10% palladium oncarbon (0.40 g) was added to stir the mixture at room temperature for 20hours in a hydrogen atmosphere. After the catalyst was removed byfiltration, the filtrate was concentrated under reduced pressure, andthe residue was dissolved in N,N-dimethylformamide (36 ml), to whichp-nitrophenyl 5-chloroindole-2-carboxylate (2.02 g) was added to stirthe mixture for 16 hours. The reaction mixture was concentrated underreduced pressure, and ethyl acetate and water were added to the residueto collect insoluble matter by filtration. The product was washed withethyl acetate to obtain crude tert-butyl(3R*,4S*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate(or(3R*,4S*)-4-amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate)(Isomer B1) (1.49 g). The organic layer of the filtrate was washed withwater and dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (methylene chloride:methanol=30:1→10:1) toobtain tert-butyl(3R*,4S*)-4-amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate(or tert-butyl(3R*,4S*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate)(Isomer B2) (0.37 g).

One of the title compounds was obtained from the Isomer B1 and thecompound obtained in Referential Example 10 in a similar manner toExample 2.

¹H-NMR (DMSO-d₆) δ: 1.25-1.50 (1H, m), 1.37 (9H, s), 1.50-1.65 (1H, m),1.75-2.20 (4H, m), 2.37 (3H, s), 2.70-3.00 (4H, m), 3.60-3.80 (3H, m),4.13 (1H, br.s), 4.43 (1H, br.s), 6.92 (1H, d, J=7.1 Hz), 7.05 (1H, s),7.17 (1H, dd, J=8.8, 2.2 Hz), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, s), 8.15(1H, d, J=7.8 Hz), 8.37 (1H, d, J=7.1 Hz), 11.78 (1H, s).

MS (FAB) m/z: 587 (M+H)⁺.

The other title compound was obtained from the Isomer B2 in the samemanner.

¹H-NMR (DMSO-d₆) δ: 1.15-1.30 (1H, m), 1.35 (9H, s), 1.45-1.60 (1H, m),1.65-1.75 (1H, m), 1.85-1.95 (1H, m), 2.05-2.20 (2H, m), 2.34 (3H, s),2.65-2.85 (4H, m), 3.55-3.70 (3H, m), 4.05-4.14 (1H, m), 4.40 (1H,br.s), 6.80 (1H, d, J=7.3 Hz), 7.15-7.25 (2H, m), 7.43 (1H, d, J=8.8Hz), 7.73 (1H, d, J=2.0 Hz), 8.05 (1H, d, J=6.6 Hz), 8.51 (1H, d, J=8.8Hz), 11.82 (1H, s).

MS (FAB) m/z: 587 (M+H)⁺.

Example 83N-((1R*,2S*)-5-Amino-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide(orN-((1R*,2S*)-4-amino-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide)hydrochloride (Stereoisomer B)

The compound (Stereoisomer B) (1.11 g) synthesized from Isomer B1 inExample 82 was suspended in methylene chloride (20 ml), and an ethanolsolution (20 ml) of hydrochloric acid was added to stir the mixture atroom temperature for 2 hours. The solvent was distilled off underreduced pressure, and the residue was purified by gel filtration(Sephadex LH-20, methanol) to obtain the title compound (1.05 g).

¹H-NMR (DMSO-d₆) δ: 1.55-1.65 (1H, m), 1.75-1.90 (2H, m), 1.95-2.20 (2H,m), 2.20-2.40 (1H, m), 2.90 (3H, s), 3.10-3.20 (1H, m), 3.20-3.50 (3H,m), 3.65-3.75 (1H, m), 4.10-4.20 (1H, m), 4.35-4.50 (1H, m), 4.55-4.65(1H, m), 4.65-4.75 (1H, m), 7.07 (1H, s), 7.17 (1H, dd, J=8.8, 2.0 Hz),7.42 (1H, d, J=8.8 Hz), 7.69 (1H, s), 8.05-8.30 (3H, br), 8.40-8.50 (2H,m), 11.70-11.90 (2H, m).

MS (FAB) m/z: 487 (M+H)⁺.

Example 84N-{(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(methylsulfonyl)amino]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamideorN-{(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-[(methylsulfonyl)amino]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(Stereoisomer B)

The compound (0.20 g) obtained in Example 83 was suspended in methylenechloride (7 ml), and triethylamine (0.16 ml) and methanesulfonylchloride (28 μl) were added to stir the mixture at room temperature for20 hours. After the reaction mixture was diluted with methylenechloride, it was washed with an aqueous solution of sodium hydroxide anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (methylene chloride:methanol=30:1→15:1) to obtain thetitle compound (67.9 mg).

¹H-NMR (DMSO-d₆) δ: 1.40-1.55 (1H, m), 1.65-1.85 (2H, m), 1.90-2.05 (2H,m), 2.15-2.25 (1H, m), 2.41 (3H, s), 2.75-2.95 (4H, m), 2.92 (3H, s),3.55-3.80 (3H, m), 4.10-4.20 (1H, m), 4.45-4.55 (1H, m), 7.08 (1H, s),7.15-7.20 (2H, m), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, s), 8.27 (1H, d,J=7.3 Hz), 8.33 (1H, d, J=8.1 Hz), 11.77 (1H, s).

MS (FAB) m/z: 565 (M+H)⁺.

Example 85N-((1R*,2S*)-5-(Acetylamino)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamideorN-((1R*,2S*)-4-(acetylamino)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(Stereoisomer B)

The compound (Stereoisomer B) (0.20 g) obtained in Example 83 wassuspended in methylene chloride (7 ml), and triethylamine (0.16 ml) andacetic anhydride (34 μl) were added to stir the mixture at roomtemperature for 20 hours. Methylene chloride and an aqueous solution ofsodium hydroxide were added to the reaction mixture to separateinsoluble matter by filtration. The organic layer of the filtrate wasseparated and dried over anhydrous sodium sulfate, and the solvent wasthen distilled off under reduced pressure. The residue was purified bycolumn chromatography on silica gel (methylenechloride:methanol=15:1→10:1) to obtain the title compound (0.12 g).

¹H-NMR (DMSO-d₆) δ: 1.35-1.50 (1H, m), 1.55-1.70 (1H, m), 1.80 (3H, s),1.80-2.05 (3H, m), 2.05-2.20 (1H, m), 2.47 (3H, s), 2.80-3.00 (4H, m),3.75-4.00 (3H, m), 4.15-4.30 (1H, m), 4.45-4.55 (1H, m), 7.07 (1H, s),7.17 (1H, dd, J=8.8, 1.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, s), 7.89(1H, d, J=7.3 Hz), 8.24 (1H, d, J=8.1 Hz), 8.31 (1H, d, J=7.3 Hz), 11.77(1H, s).

MS (FAB) m/z: 528 (M+H)⁺.

Example 86N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[methoxy(methyl)amino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (250 mg) obtained in Example 58 was dissolved inN,N-dimethylformamide (5 ml), and N,O-dimethylhydroxylaminehydrochloride (142 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (111 mg), 1-hydroxybenzotriazole monohydrate (89 mg) andN-methylmorpholine (213 ml) were added to stir the mixture at roomtemperature for 19 hours. After the reaction mixture was concentrated,an aqueous solution of sodium hydrogencarbonate was added to the residueto conduct extraction with ethyl acetate. After the resultant organiclayer was washed with saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (methylene chloride:methanol=47:3→23:2) to obtain a colorlessamorphous solid (179 mg). This product was dissolved inmethanol-tetrahydrofuran, and 1N ethanol solution (960 ml) ofhydrochloric acid was added to obtain the title compound.

¹H-NMR (DMSO-d₆) δ: 1.57-1.91 (4H, m), 1.96-2.00 (1H, m), 2.10-2.21 (1H,m), 2.92 (3H, s), 2.93-3.03 (2H, m), 3.08 (3H, s), 3.10-3.28 (2H, m),4.16-4.19 (1H, m), 4.50-4.52 (1H, m), 4.69 (1H, br.s), 7.06 (1H, s),7.17 (1H, dd, J=8.8, 1.5 Hz), 7.42 (1H, d, J=8.8 Hz), 7.70 (1H, s), 8.33(1H, br.s), 8.41 (1H, d, J=7.8 Hz), 11.81 (1H, br.s).

MS (ESI) m/z: 559 (M+H)⁺.

Example 87N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(2,2-dimethylhydrazino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example 58and N,N-dimethylhydrazine in a similar manner to Example 57.

¹H-NMR (DMSO-d₆) δ: 1.49-1.54 (1H, m), 1.76-1.81 (2H, m), 1.89-1.93 (2H,m), 2.07-2.17 (1H, m), 2.33-3.60 (14H, m), 4.15-4.19 (1H, m), 4.40-4.47(2H, m), 4.70-4.72 (1H, m), 7.04 (1H, s), 7.17 (1H, dd, J=8.5, 2.0 Hz),7.42 (1H, d, J=8.5 Hz), 7.70 (1H, s), 8.17-8.22 (1H, m), 8.41-8.43 (1H,m), 11.80 (1H, br.s).

MS (ESI) m/z: 558 (M+H)⁺.

Example 886-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-2-quinolinecarboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 145 with an ethanol solution of hydrochloric acid ina similar manner to Example 49 and then condensing it with the compoundobtained in Referential Example 10.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.75-1.90 (3H, m), 1.90-2.00 (1H,m), 2.00-2.20 (1H, m), 2.80 (3H, s), 2.90 (3H, s), 2.99 (3H, s),3.10-3.30 (5H, m), 3.56 (1H, br), 4.10-4.20 (1H, m), 4.40-4.70 (2H, m),7.88 (2H, s), 8.15 (1H, d, J=8.6 Hz), 8.22 (1H, s), 8.52 (1H, d, J=8.6Hz), 8.72 (1H, d, J=8.3 Hz), 8.89 (1H, d, J=8.3 Hz).

MS (FAB) m/z: 555 (M+H)⁺.

Example 89N-{(1R,2S,5S)-2-{[(5-Chloro-4-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 144 with the compound obtained in ReferentialExample 274 in a similar manner to Referential Example 91 and treatingthe resultant compound with a 4N dioxane solution of hydrochloric acidand then with the compound obtained in Referential Example 10.

¹H-NMR (DMSO-d₆) δ: 1.24-1.98 (6H, m), 2.33-3.33 (6H, m), 2.81 (3H, s),2.90 (3H, s), 2.99 (3H, s), 4.12 (1H, br.s), 4.30-4.70 (1H, m), 4.60(1H, br.s), 7.21 (1H, s), 7.27 (2H, br.s), 8.37 (1H, d, J=8.1 Hz), 8.43(1H, d, J=7.6 Hz), 12.11 (1H, s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 907-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)isoquinoline-3-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 146 with an ethanol solution of hydrochloric acid ina similar manner to Example 49 and then condensing it with the compoundobtained in Referential Example 10.

¹H-NMR (DMSO-d₆) δ: 1.45-1.65 (1H, m), 1.70-1.85 (3H, m), 1.95-2.10 (1H,m), 2.10-2.20 (1H, m), 2.80 (3H, s), 2.92 (3H, s), 2.96 (3H, s),2.95-3.10 (1H, m), 3.10-3.40 (3H, m), 3.70-3.80 (1H, m), 4.20-4.30 (1H,m), 4.40-4.60 (2H, m), 4.65-4.80 (1H, m), 7.83-7.93 (1H, m), 8.26 (1H,d, J=8.8 Hz), 8.38 (1H, s), 8.60 (1H, s), 8.85-9.00 (2H, m), 9.30-9.40(1H, m).

MS (FAB) m/z: 555 (M+H)⁺.

Example 91N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}tetrahydrofuran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (0.1 g) obtained in Referential Example 10,1-hydroxybenzotriazole monohydrate (78 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2 g) weresuccessively added to a solution of the compound (0.12 g) obtained inReferential Example 172 in N,N-dimethylformamide (20 ml), and themixture was stirred at room temperature for 1 day. After the reactionmixture was concentrated, and the resultant residue was diluted withchloroform-methanol (9:1) and washed with a saturated aqueous solutionof sodium hydrogencarbonate and saturated aqueous solution of sodiumchloride, the resultant organic layer was dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(chloroform:methanol=95:5) to obtain a free base of the title compound.This product was treated with an ethanol solution of hydrochloric acidto obtain the title compound (0.1 g).

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 2.70-2.90 (4H, m), 3.67 (1H, s), 3.70(1H, s), 3.86 (1H, dd, J=9.2, 6.3 Hz), 3.97 (1H, dd, J=9.7, 4.1 Hz),4.15 (1H, dd, J=9.7, 5.8 Hz), 4.24 (1H, dd, J=9.2, 7.0 Hz), 4.75-4.89(1H, m), 4.92-5.03 (1H, m), 6.88 (1H, s), 7.20 (1H, dd, J=8.8, 2.0 Hz),7.33 (1H, d, J=8.8 Hz), 7.35-7.43 (1H, m), 7.58 (1H, d, J=2.0 Hz), 7.64(1H, d, J=7.1 Hz), 9.38 (1H, s).

MS (FAB) m/z: 460 (M+H⁺).

Example 92N-((3S,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}tetrahydrofuran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 183 in accordance with the processes of ReferentialExample 172 and Example 91.

¹H-NMR (CDCl₃) δ: 2.51 (3H, s), 2.83 (2H, t, J=5.3 Hz), 2.93 (2H, t,J=5.3 Hz), 3.72 (2H, s), 3.78-3.89 (2H, m), 4.31 (1H, dd, J=9.2, 7.3Hz), 4.41-4.56 (2H, m), 4.63-4.75 (1H, m), 6.88 (1H, s), 7.22 (1H, dd,J=8.8, 2.0 Hz), 7.32 (1H, d, J=8.8 Hz), 7.35-7.46 (1H, m), 7.55 (1H, d,J=7.1 Hz), 7.60 (1H, d, J=2.0 Hz), 9.38 (1H, s).

MS (FAB) m/z: 460 (M+H⁺).

Example 93N-((3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}tetrahydrofuran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 187 in accordance with the processes of ReferentialExample 172 and Example 91.

¹H-NMR and MS (FAB): The same as those of the enantiomer in Example 92.

Example 94 tert-Butyl(3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 193 and the compound obtained in Referential Example10 in accordance with the process of Example 91.

Melting point: 190-192° C.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.46 (3H, s), 2.74-2.81 (4H, m),3.24-3.37 (2H, m), 3.54-3.70 (2H, m), 3.96-4.00 (1H, m), 4.15-4.23 (1H,m), 4.50-4.65 (1H, m), 4.77-4.82 (1H, m), 6.79, 6.87 (total 1H, each s),7.12-7.95 (5H, m), 9.91, 9.97 (total 1H, each s).

MS (FAB) m/z: 559 (M+H⁺).

Example 95N-((3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}pyrrolidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (170 mg) obtained in Example 94 was dissolved in methylenechloride (3 ml), and trifluoroacetic acid (2 ml) was added at roomtemperature to stir the mixture for 1 hour. After concentrating thereaction mixture, chloroform and a saturated aqueous solution of sodiumhydrogencarbonate were added. The resultant organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by preparativethin-layer chromatography on silica gel (chloroform:methanol:water=7:3:1under layer). A methanol solution of hydrochloric acid was added to theresultant intended product to obtain the title compound (90 mg) as ahydrochloride (NMR was measured in the form of a free base).

Melting point: 248-250° C. (decomposed).

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 2.70-2.80 (4H, m), 2.97-3.05 (2H, m),3.46-3.68 (4H, m), 4.49-4.52 (1H, m), 4.60-4.65 (1H, m), 6.86 (1H, s),7.05-7.08 (1H, m), 7.20 (1H, d, J=8.5 Hz), 7.44 (1H, s), 7.89 (2H, br),10.51 (1H, br).

MS (FAB) m/z: 459 (M+H⁺).

Example 96N-((3S,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-oxotetrahydrofuran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by removing the tert-butoxycarbonylgroup of the compound obtained in Referential Example 196 in a similarmanner to Referential Example 69 and reacting the resultant product withthe compound obtained in Referential Example 10 in a similar manner toExample 91.

¹H-NMR (DMSO-d₆) δ: 2.90 (3H, s), 3.02-3.17 (2H, m), 3.23-3.34 (4H, m),4.20 (1H, t, J=8.6 Hz), 4.61 (1H, t, J=8.6 Hz), 4.92-5.01 (1H, m),5.14-5.26 (1H, m), 7.09 (1H, s), 7.19 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H,d, J=8.8 Hz), 7.73 (1H, d, J=2.0 Hz), 9.27 (1H, d, J=6.8 Hz), 9.35 (1H,d, J=6.8 Hz), 11.22-11.33 (1H, m), 11.89 (1H, s).

MS (FAB) m/z: 474 (M+H⁺).

Example 97N-((3S,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-2-oxotetrahydrofuran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by removing the tert-butoxycarbonylgroup of the compound obtained in Referential Example 197 in a similarmanner to Referential Example 69 and reacting the resultant product with5-chloroindole-2-carboxylic acid in a similar manner to Example 91.

¹H-NMR (DMSO-d₆) δ: 2.52 (3H, s), 2.83 (2H, t, J=5.9 Hz), 2.91-3.00 (2H,m), 3.73 (2H, s), 4.23 (1H, t, J=8.6 Hz), 4.40-4.53 (1H, m), 4.96 (1H,dd, J=10.8, 5.2 Hz), 5.16 (1H, dd, J=9.2, 7.3 Hz), 7.01 (1H, s), 7.25(1H, dd, J=8.8, 2.0 Hz), 7.34 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=2.0 Hz),8.01 (1H, d, J=5.4 Hz), 8.51-8.63 (1H, m), 9.22 (1H, s).

MS (FAB) m/z: 474 (M+H⁺).

Example 98 Ethyl(3S,4R)-2-(3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}-2-oxopyrrolidin-1-yl)acetatehydrochloride

The title compound was obtained from the compound obtained inReferential Example 199 and the compound obtained in Referential Example10 in a similar manner to Example 91. NMR was measured in the form of afree base.

¹H-NMR (DMSO-d₆) δ: 1.19 (3H, t, J=7.1 Hz), 2.35 (3H, s), 2.71-2.84 (2H,m), 2.80-2.90 (2H, m), 3.40 (1H, d, J=10.3 Hz), 3.61 (2H, d, J=10.8 Hz),3.84 (1H, dd, J=10.3, 5.6 Hz), 4.01-4.23 (4H, m), 4.80-4.94 (1H, m),5.04 (1H, t, J=8.6 Hz), 7.01 (1H, s), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.40(1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.0 Hz), 8.73 (1H, d, J=8.6 Hz), 8.90(1H, d, J=8.8 Hz), 11.86 (1H, s).

MS (FAB) m/z: 559 (M+H⁺).

Example 99N-((3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-methyl-5-oxopyrrolidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained inReferential Example 201 and the compound obtained in Referential Example10 in a similar manner to Example 91.

¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 2.77-2.82 (2H, m), 2.86-2.91 (5H, m),3.69 (2H, d, J=1.2 Hz), 4.39-4.54 (3H, m), 4.93-4.98 (1H, m), 6.98 (1H,d, J=1.2 Hz), 7.05-7.34 (3H, m), 7.63 (1H, d, J=2.0 Hz), 8.11 (1H, d,J=7.8 Hz), 9.00 (1H, s)

MS (FAB) m/z: 487 (M+H⁺).

Example 100 Methyl2-[((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)sulfonyl]acetate

The compound (230 mg) obtained in Example 95 and triethylamine (0.10 ml)were dissolved in methylene chloride (6.9 ml), and the mixture wascooled with ice. Methoxycarbonylmethanesulfonyl chloride (Synthesis, p.321, 1975) (105 mg) was added, and the resultant mixture was warmed toroom temperature and stirred overnight. The reaction mixture was dilutedwith chloroform, washed with water and saturated aqueous solution ofsodium chloride and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by preparative thin-layer chromatography on silica gel(chloroform:methanol=20:1) and powdered with methanol-water to obtainthe title compound (150 mg).

¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 2.76-2.86 (4H, m), 3.49-3.73 (4H, m),3.87 (3H, s), 3.94-3.98 (1H, m), 4.08-4.11 (1H, m), 4.13 (2H, s),4.69-4.72 (1H, m), 4.88-4.91 (1H, m), 6.89 (1H, s), 7.12-7.15 (1H, m),7.27-7.28 (1H, m), 7.50 (1H, s), 7.81-7.86 (2H, m), 9.92 (1H, s).

MS (FAB) m/z: 595 (M+H⁺).

Example 1012-[((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)sulfonyl]aceticacid

The compound (100 mg) obtained in Example 100 was dissolved intetrahydrofuran (4 ml)-water (1 ml), and the mixture was cooled withice. Lithium hydroxide monohydrate (7.8 mg) was added, and the resultantmixture was heated to room temperature and stirred for 4 hours. Afterthe reaction mixture was neutralized with 1N hydrochloric acid, it wasconcentrated. Deposits were collected by filtration, washed with waterand 50% ethanol and dried overnight at 50° C. under reduced pressure toobtain the title compound (87 mg).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.92 (4H, s), 3.34-3.43 (4H, m),3.76-3.85 (2H, m), 4.27 (each 1H, AB type d, J=14.5 Hz), 4.65-4.71 (1H,m), 4.78-4.84 (1H, m), 7.14 (1H, s), 7.18 (1H, d, J=8.8 Hz), 7.40 (1H,d, J=8.8 Hz), 7.72 (1H, s), 8.87 (1H, d, J=7.8 Hz), 9.12 (1H, d, J=8.2Hz), 11.83 (1H, s).

Example 102 Methyl2-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)acetate

The compound (230 mg) obtained in Example 95 and potassium carbonate (90mg) were dissolved in N,N-dimethylformamide (4.6 ml), and the mixturewas cooled with ice. Methyl bromoacetate (0.062 ml) was added, and theresultant mixture was stirred for 45 minutes. The reaction mixture wasdiluted with ethyl acetate, washed with water and saturated aqueoussolution of sodium chloride and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by preparative thin-layer chromatographyon silica gel (chloroform:methanol=10:1) and solidifier withmethanol-water to obtain the title compound (190 mg).

¹H-NMR (CDCl₃) δ: 2.35 (2H, s), 2.48 (3H, s), 2.73-2.95 (4H, m),3.34-3.42 (2H, m), 3.46 (2H, q, J=6.5 Hz), 3.67 (2H, q, J=6.5 Hz), 3.75(3H, s), 4.57-4.71 (2H, m), 6.91 (1H, s), 7.10-7.13 (1H, m), 7.31 (1H,d, J=9.0 Hz), 7.53 (1H, s), 7.77 (1H, d, J=8.0 Hz), 7.87 (1H, d, J=6.8Hz), 10.22 (1H, s).

MS (FAB) m/z: 531 (M+H⁺).

Example 1032-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)aceticacid

The title compound was obtained from the compound obtained in Example102 in a similar manner to Example 101.

¹H-NMR (DMSO-d₆) δ: 2.42 (3H, s), 2.69-2.87 (6H, m), 3.13 (1H, t, J=9.0Hz), 3.22 (1H, t, J=9.0 Hz), 3.33 (each 1H, AB type d, J=6.8 Hz), 3.72(2H, s), 4.53-4.60 (1H, m), 4.65-4.72 (1H, m), 7.16-7.20 (2H, m), 7.42(1H, d, J=8.8 Hz), 7.70 (1H, s), 8.85 (1H, d, J=7.5 Hz), 9.00 (1H, d,J=8.3 Hz), 11.79 (1H, s).

Example 104 Methyl3-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propionate

The title compound was obtained from the compound obtained in Example 95and methyl 3-bromopropionate in a similar manner to Example 102.

¹H-NMR (CDCl₃) δ: 1.96-2.20 (2H, m), 2.49 (3H, s), 2.61-2.96 (8H, m),3.17-3.21 (2H, m), 3.62-3.72 (2H, m), 3.69 (3H, s), 4.46-4.49 (1H, m),4.56-4.61 (1H, m), 6.87 (1H, s), 7.05-7.14 (1H, m), 7.32 (1H, d, J=9.2Hz), 7.53 (1H, s), 7.65-7.71 (2H, m), 10.02 (1H, s).

MS (FAB) m/z: 545 (M+H⁺).

Example 1053-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propionicacid

The title compound was obtained from the compound obtained in Example104 in a similar manner to Example 101.

¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 2.39-2.84 (10H, m), 2.93 (1H, t, J=8.8Hz), 3.05 (1H, t, J=8.8 Hz), 3.65 (2H, s), 4.51-4.56 (1H, m), 4.63-4.68(1H, m), 7.16-7.19 (2H, m), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, s), 8.81(1H, d, J=7.8 Hz), 8.97 (1H, d, J=8.3 Hz), 11.75 (1H, s).

Example 106 Ethyl3-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)-3-oxopropionate

The title compound was obtained from the compound obtained in Example 95and ethylmalonyl chloride in a similar manner to Example 100.

¹H-NMR (DMSO-d₆) δ: 1.20 (3H, t, J=7.0 Hz), 2.37 (3H, s), 2.73-2.75 (2H,m), 2.82-2.84 (2H, m), 3.35-3.38 (2H, m), 3.64 (2H, s), 3.68-3.83 (2H,m), 3.91-4.00 (2H, m), 4.10 (2H, q, J=7.0 Hz), 4.61-4.84 (2H, m), 7.13(1H, s), 7.18 (1H, dd, J=8.5, 2.0 Hz), 7.41 (1H, d, J=8.5 Hz), 7.72 (1H,s), 8.73 (1H, t, J=9.0 Hz), 9.10 (1H, d, J=9.0 Hz), 11.79 (1H, s).

Example 1073-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)-3-oxopropionicacid

The title compound was obtained from the compound obtained in Example106 in a similar manner to Example 101.

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 2.77 (2H, s), 2.85 (2H, s), 3.29-3.55(4H, m), 3.68 (2H, s), 3.82-4.01 (2H, m), 4.62-4.68 (1H, m), 4.77-4.86(1H, m), 7.14 (1H, s), 7.18 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=8.8 Hz),7.72 (1H, s), 8.75 (1H, t, J=8.8 Hz), 9.12 (1H, d, J=7.8 Hz), 11.81 (1H,s).

Example 108 Methyl1-[((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)methyl]cyclopropanecarboxylate

The title compound was obtained from the compound obtained in Example 95and methyl 1-(bromomethyl)cyclopropanecarboxylate in a similar manner toExample 102.

¹H-NMR (CDCl₃) δ: 0.78-0.79 (2H, m), 1.24-1.26 (2H, m), 2.49 (3H, s),2.62-2.88 (6H, m), 3.20-3.28 (2H, m), 3.66 (3H, s), 3.61-3.75 (4H, m),4.45-4.62 (2H, m), 6.86 (1H, s), 7.12-7.15 (1H, m), 7.24-7.28 (1H, m),7.52 (1H, d, J=8.5 Hz), 7.54 (1H, s), 7.69 (1H, d, J=8.0 Hz), 10.00 (1H,s).

MS (ESI) m/z: 571 (M+H⁺).

Example 1091-[((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)methyl]cyclopropanecarboxylicacid

The title compound was obtained from the compound obtained in Example108 in a similar manner to Example 101.

¹H-NMR (DMSO-d₆) δ: 0.73-0.78 (2H, m), 1.04-1.07 (2H, m), 2.37 (3H, s),2.65-2.84 (6H, m), 3.11-3.20 (4H, m), 3.64 (2H, s), 4.59-4.74 (2H, m),7.16 (1H, s), 7.17 (1H, d, J=8.5 Hz), 7.40 (1H, d, J=8.5 Hz), 7.70 (1H,s), 8.84 (1H, d, J=7.5 Hz), 9.12 (1H, d, J=7.5 Hz), 11.77 (1H, s).

Example 110 tert-Butyl(3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 193 and Referential Example 148 in a similar mannerto Example 91.

¹H-NMR (CDCl₃) δ: 1.12 (6H, d, J=6.6 Hz), 1.47 (9H, s), 2.83-2.88 (4H,m), 2.94-2.99 (1H, m), 3.20-3.29 (1H, m), 3.31-3.42 (1H, m), 3.75-3.81(2H, m), 3.98 (1H, t, J=8.5 Hz), 4.15-4.35 (2H, m), 4.50-4.65 (1H, m),6.85, 6.91 (total 1H, each s), 7.15-7.90 (5H, m), 9.41, 9.50 (total 1H,each s).

Example 111N-((3R,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}pyrrolidin-3-yl)-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained in Example110 in a similar manner to Example 95.

¹H-NMR (CDCl₃) δ: 1.13 (6H, d, J=6.3 Hz), 2.85 (4H, br.s), 2.96-3.05(3H, m), 4.51-4.52 (1H, m), 4.76-4.80 (2H, m), 5.36-5.39 (2H, m),5.53-5.58 (1H, m), 7.17-7.19 (1H, m), 7.27-7.31 (2H, m), 7.57 (1H, s),7.64 (2H, br), 9.82 (1H, br).

Example 112 Ethyl3-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propionate

The title compound was obtained from the compound obtained in Example111 and ethyl 3-bromopropionate in a similar manner to Example 102.

¹H-NMR (CDCl₃) δ: 1.14 (6H, d, J=6.5 Hz), 1.26 (3H, t, J=7.0 Hz), 2.51(3H, t, J=7.0 Hz), 2.63 (1H, dd, J=9.5, 6.5 Hz), 2.73-2.91 (6H, m),2.95-3.02 (1H, m), 3.22 (2H, q, J=7.0 Hz), 3.81 (each 1H, AB type d,J=14.5 Hz), 4.16 (2H, q, J=7.0 Hz), 4.40-4.45 (1H, m), 4.52-4.59 (1H,m), 6.88 (1H, d, J=2.0 Hz), 7.17-7.19 (1H, m), 7.30-7.32 (2H, m), 7.59(1H, s), 7.62 (1H, s), 9.56 (1H, s).

MS (FAB) m/z: 587 (M+H⁺).

Example 1133-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propionicacid

The title compound was obtained from the compound obtained in Example112 in a similar manner to Example 101.

¹H-NMR (DMSO-d₆) δ: 1.04 (6H, d, J=6.6 Hz), 2.40 (2H, q, J=7.0 Hz), 2.50(4H, s), 2.60-2.74 (4H, m), 2.90-2.94 (2H, m), 3.02-3.06 (1H, m),3.20-3.35 (2H, m), 4.50-4.53 (1H, m), 4.61-4.65 (1H, m), 7.15-7.18 (2H,m), 7.41 (1H, d, J=8.8 Hz), 7.68 (1H, s), 8.78 (1H, d, J=7.5 Hz), 8.90(1H, d, J=8.0 Hz), 11.73 (1H, s).

Example 114N-((3R,4R)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}pyrrolidin-3-yl)-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example111 and acetic anhydride in a similar manner to Example 100.

Melting point: 254-258° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.34-1.37 (6H, m), 1.96 (3H, s), 3.30-3.55 (5H, m),3.66-3.82 (3H, m), 3.95 (1H, q, J=8.3 Hz), 4.45-4.82 (4H, m), 7.15 (1H,s), 7.18 (1H, d, J=9.0 Hz), 7.41 (1H, d, J=9.0 Hz), 7.71 (1H, s),8.75-8.81 (1H, m), 9.21 (1H, d, J=8.0 Hz), 11.32 (1H, br), 11.83 (1H, d,J=7.3 Hz).

MS (FAB) m/z: 529 (M+H⁺).

Example 115N-[(3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)pyrrolidin-3-yl]-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example111 and methanesulfonyl chloride in a similar manner to Example 100.

Melting point: 230-235° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.32-1.36 (6H, m), 3.32 (3H, s), 3.43-3.46 (5H, m),3.68-3.75 (4H, m), 4.48 (1H, m), 4.62-4.72 (2H, m), 4.83 (1H, t, J=5.5Hz), 7.14 (1H, s), 7.18 (1H, d, J=8.6 Hz), 7.40 (1H, d, J=8.6 Hz), 7.72(1H, s), 8.82 (1H, br), 9.20 (1H, d, J=8.3 Hz), 11.30 (1H, br), 11.86(1H, d, J=7.5 Hz).

MS (FAB) m/z: 565 (M+H⁺).

Example 116 Ethyl(3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidine-1-carboxylatehydrochloride

The title compound was obtained from the compound obtained in Example111 and ethyl chloroformate in a similar manner to Example 100.

Melting point: 225-228° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.20 (3H, t, J=7.0 Hz), 1.31-1.37 (6H, m), 3.33-3.45(5H, m), 3.66-3.75 (4H, m), 4.05 (2H, q, J=7.0 Hz), 4.45-4.77 (4H, m),7.15 (1H, s), 7.17 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.71(1H, d, J=2.0 Hz), 8.77 (1H, d, J=7.0 Hz), 9.20 (1H, d, J=8.0 Hz), 11.30(1H, br), 11.83 (1H, d, J=7.5 Hz).

MS (FAB) m/z: 559 (M+H⁺).

Example 117 tert-Butyl(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 207 and Referential Example 10 in a similar mannerto Example 91.

Melting point: 152-154° C. (decomposed).

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 1.62-1.80 (1H, m), 2.23-2.30 (1H, m),2.52 (3H, s), 2.75-3.05 (5H, m), 3.10-3.25 (1H, m), 3.68-3.82 (2H, m),4.15-4.45 (4H, m), 6.89 (1H, s), 7.19 (1H, dd, J=8.8, 1.8 Hz), 7.32 (1H,d, J=8.8 Hz), 7.92 (1H, d, J=1.8 Hz), 7.75 (1H, br.s), 8.21 (1H, br.s),9.39 (1H, s).

MS (ESI) m/z: 573 (M+H)⁺.

Example 118N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidedihydrochloride

The title compound was obtained from the compound obtained in Example117 in a similar manner to Example 95.

Melting point: 240-258° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.85-2.00 (1H, m), 2.05-2.20 (2H, m), 2.93 (3H, s),3.05-3.60 (7H, m), 3.65-3.75 (1H, m), 4.10-4.52 (2H, m), 4.60-4.75 (2H,m), 7.10-7.21 (2H, m), 7.43 (1H, d, J=8.6 Hz), 7.70 (1H, s), 8.50 (1H,br.d, J=7.8 Hz), 8.90-9.05 (2H, m), 9.27 (1H, br.s), 11.9 (1H, br.d,J=13.4 Hz).

MS (ESI) m/z: 473 (M+H)⁺.

Example 119 tert-Butyl(3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 208 and 5-chloroindole-2-carboxylic acid in asimilar manner to Example 91.

Melting point: 187-189° C. (decomposed).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.72-1.90 (1H, m), 2.00 (1H, br.s),2.00-2.10 (1H, m), 2.45 (3H, s), 2.60-2.70 (2H, m), 2.70-2.80 (2H, m),3.23 (1H, t, J=10.8 Hz), 3.35-3.50 (1H, m), 3.50-3.72 (2H, m), 3.90-4.20(2H, m), 4.30-4.40 (1H, m), 4.45-4.55 (1H, m), 6.85 (1H, d, J=1.5 Hz),7.17 (1H, dd, J=8.8, 1.9 Hz), 7.20-7.30 (1H, m), 7.33 (1H, d, J=8.8 Hz),7.58 (1H, d, J=1.9 Hz), 10.17 (1H, s).

MS (ESI) m/z: 573 (M+H⁺).

Example 120N-((3R*,4S*)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}piperidin-4-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidedihydrochloride

The title compound was obtained from the compound obtained in Example119 in a similar manner to Example 95.

Melting point: 276-278° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.77-1.88 (1H, m), 2.40-2.50 (2H, m), 2.89 (3H, s),2.90-3.20 (4H, m), 3.30-3.50 (2H, m), 3.63 (1H, br.s), 4.33-4.47 (2H,m), 4.62-4.75 (2H, m), 7.18 (1H, dd, J=8.8, 1.9 Hz), 7.42 (1H, d, J=8.8Hz), 7.48 (1H, br.s), 7.71 (1H, d, J=1.9 Hz), 8.66 (1H, br.s), 8.95 (1H,d, J=8.1 Hz), 9.20-9.30 (1H, m), 9.45-9.70 (1H, m), 11.61 (1H, s), 11.90(1H, s).

MS (ESI) m/z: 473 (M+H)⁺.

Example 121 tert-Butyl(3R*,4S*)-4-{[(5-fluoroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 209 and Referential Example 10 in a similar mannerto Example 91.

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 1.65-1.78 (1H, m), 2.23-2.32 (1H, br),2.52 (3H, s), 2.78-3.03 (5H, m), 3.15-3.24 (1H, br), 3.68-3.82 (2H, br),4.16-4.45 (4H, br), 6.91 (1H, s), 7.02 (1H, td, J=9.0, 2.7 Hz), 7.30(1H, dd, J=9.0, 2.7 Hz), 7.34 (1H, dd, J=9.0, 4.4 Hz), 7.65-7.90 (1H,br), 8.10-8.40 (1H, br), 9.31-9.41 (1H, br).

MS (ESI) m/z: 557 (M+H⁺).

Example 122N-((3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidedihydrochloride

The title compound was obtained from the compound obtained in Example121 in a similar manner to Example 95.

Melting point: 236-245° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.85-1.98 (1H, br), 2.06-2.18 (1H, br), 2.89 (3H,s), 3.05-3.75 (8H, s), 4.34-4.54 (2H, br), 4.60-4.75 (2H, br), 7.04 (1H,td, J=9.3, 2.4 Hz), 7.15 (1H, br.s), 7.37-7.44 (2H, m), 8.46 (1H, d,J=7.8 Hz), 8.88-9.00 (1H, br), 9.09-9.27 (2H, br), 11.55-11.75 (1H, br),11.76-11.84 (1H, br).

MS (FAB) m/z: 457 (M+H⁺).

Example 123N-((3R*,4S*)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and acetic anhydride in a similar manner to Example 100.

Melting point: 215-225° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.65-1.85 (1H, m), 1.88, 2.06 (total 3H, each s),1.90-2.10 (1H, m), 2.91 (3H, s), 3.00-3.30 (2H, m), 3.30-3.55 (2H, m),3.60-3.90 (3H, m), 3.98-4.50 (4H, m), 4.65-4.75 (1H, m), 7.09 (1H, d,J=15.6 Hz), 7.17 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=8.8 Hz), 7.71 (1H,s), 8.23-8.53 (2H, m), 11.20-11.55 (1H, m), 11.85 (1H, br.d, J=5.4 Hz).

MS (ESI) m/z: 515 (M+H⁺).

Example 124N-((3R*,4S*)-1-Acetyl-3-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-4-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example120 and acetic anhydride in a similar manner to Example 100.

Melting point: 225-250° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.65-1.80 (1H, m), 1.81, 2.05 (total 3H, each s),2.00-2.20 (1H, m), 2.70-2.85 (1H, m), 2.89 (3H, s), 3.00-3.20 (2H, m),3.20-3.50 (2H, m), 3.64 (1H, br.s), 3.78-4.30 (2H, m), 4.30-4.50 (3H,m), 4.55-4.75 (1H, m), 7.05-7.23 (2H, m), 7.38-7.48 (1H, m), 7.70-7.80(1H, m), 7.79, 8.12 (total 1H, each d, J=6.8 Hz), 8.73, 8.83 (total 1H,each d, J=8.3 Hz), 11.20-11.50 (1H, m), 11.89, 11.92 (total 1H, each s).

MS (FAB) m/z: 515 (M+H⁺).

Example 125N-((3R*,4S*)-1-Acetyl-4-{[(5-fluoroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example122 and acetic anhydride in a similar manner to Example 100.

Melting point: 202° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.67-1.85 (1H, m), 1.87 (1.5H, s), 1.87-2.10 (1H,m), 2.06 (1.5H, s), 2.88-2.96 (3H, br.s), 3.05-3.30 (2H, m), 3.32-3.83(5H, br), 3.97-4.33 (2H, m), 4.35-4.50 (2H, br), 4.67-4.78 (1H, br),7.01-7.14 (2H, m), 7.38-7.44 (2H, m), 8.25-8.50 (2H, m), 10.85-11.15(1H, br), 11.72-11.80 (1H, br).

MS (FAB) m/z: 499 (M+H⁺).

Example 126N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and methanesulfonyl chloride in a similar manner to Example 100.

Melting point: 225-230° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.80-1.90 (1H, m), 2.05-2.15 (1H, m), 2.30-2.80 (5H,m), 2.85-3.80 (9H, m), 4.20-4.90 (4H, m), 7.08 (1H, d, J=1.7 Hz), 7.18(1H, dd, J=8.7, 1.7 Hz), 7.42 (1H, d, J=8.7 Hz), 7.77 (1H, s), 8.02-8.20(1H, m), 8.40-8.50 (1H, m), 11.00-11.60 (1H, m), 11.87 (1H, s).

MS (ESI) m/z: 551 (M+H⁺).

Example 127N-[(3R*,4S*)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)piperidin-4-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example120 and methanesulfonyl chloride in a similar manner to Example 100.

Melting point: 228-245° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.75-1.85 (1H, m), 2.25-2.40 (1H, m), 2.40-2.60 (2H,m), 2.76 (3H, br.s), 2.90 (3H, s), 2.93-3.05 (3H, m), 3.12 (1H, d,J=10.6 Hz), 3.55-3.80 (2H, m), 4.25-4.40 (4H, m), 7.17 (1H, d, J=1.7Hz), 7.19 (1H, dd, J=8.7, 2.0 Hz), 7.43 (1H, d, J=8.7 Hz), 7.74 (1H, d,J=2.0 Hz), 8.03 (1H, d, J=6.6 Hz), 8.78 (1H, d, J=7.4 Hz), 10.90-11.20(1H, br.s), 11.89 (1H, s).

MS (ESI) m/z: 551 (M+H⁺).

Example 128N-[(3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)piperazin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example122 and methanesulfonyl chloride in a similar manner to Example 100.

Melting point: 216-250° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.80-1.90 (1H, m), 2.01-2.12 (1H, m), 2.92 (3H, s),2.94 (3H, s), 3.00-3.80 (8H, m), 4.28-4.53 (3H, m), 4.60-4.80 (1H, br),7.01-7.12 (2H, m), 7.37-7.44 (2H, m), 8.00-8.18 (1H, br), 8.39-8.50 (1H,br), 11.00-11.60 (1H, br), 11.72-11.80 (1H, br).

MS (FAB) m/z: 535 (M+H⁺).

Example 129 Methyl(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylatehydrochloride

The title compound was obtained from the compound obtained in Example118 and methyl chloroformate in a similar manner to Example 100.

Melting point: 248-253° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.65-1.78 (1H, m), 1.88-2.03 (1H, m), 2.90 (3H, s),3.00-3.80 (9H, m), 3.80-3.90 (1H, m), 3.95-4.08 (1H, m), 4.20-4.70 (4H,m), 7.10 (1H, s), 7.17 (1H, dd, J=8.8, 1.8 Hz), 7.42 (1H, d, J=8.8 Hz),7.71 (1H, d, J=1.8 Hz), 8.29 (1H, br.s), 8.41 (1H, d, J=8.1 Hz), 11.29(1H, br.s), 11.85 (1H, s).

MS (ESI) m/z: 531 (M+H⁺).

Example 130 Ethyl(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylatehydrochloride

The title compound was obtained from the compound obtained in Example118 and ethyl chloroformate in a similar manner to Example 100.

Melting point: 215-225° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 0.85-1.30 (3H, m), 1.65-1.78 (1H, m), 1.90-2.03 (1H,m), 2.90 (3H, s), 3.10-3.40 (4H, m), 3.48 (1H, br.s), 3.65 (1H, br.s),3.75-4.15 (4H, m), 4.25 (1H, br.s), 4.32-4.50 (2H, m), 4.66 (1H, br.s),7.09 (1H, s), 7.18 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.71(1H, d, J=2.0 Hz), 8.23 (1H, br.s), 8.45 (1H, br.d, J=8.1 Hz), 11.50(1H, br.s), 11.86 (1H, s).

MS (ESI) m/z: 545 (M+H⁺).

Example 131 2-Methoxyethyl(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylatehydrochloride

The title compound was obtained from the compound obtained in Example118 and 2-methoxyethyl chloroformate in a similar manner to Example 100.

Melting point: 224-226° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.68-1.78 (1H, m), 1.90-2.03 (1H, m), 2.89 (3H, s),3.00-3.75 (11H, m), 3.80-3.90 (1H, m), 3.95-4.18 (3H, m), 4.20-4.70 (4H,m), 7.10 (1H, s), 7.17 (1H, dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz),7.71 (1H, d, J=2.0 Hz), 8.26 (1H, br.s), 8.42 (1H, d, J=7.8 Hz), 11.30(1H, br.s), 11.86 (1H, s).

MS (ESI) m/z: 575 (M+H⁺).

Example 132 Ethyl(3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylatehydrochloride

The title compound was obtained from the compound obtained in Example120 and ethyl chloroformate in a similar manner to Example 100.

Melting point: 213-225° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 0.75-1.30 (3H, m), 1.60-1.72 (1H, m), 2.12-2.25 (1H,m), 2.89 (3H, s), 2.95-3.20 (4H, m), 3.40-3.88 (4H, m), 3.90-4.10 (2H,m), 4.10-4.30 (2H, m), 4.30-4.40 (1H, m), 4.40-4.80 (1H, m), 7.10 (1H,s), 7.18 (1H, dd, J=8.8, 2.0 Hz), 7.43 (1H, d, J=8.8 Hz), 7.74 (1H, s),8.03 (1H, d, J=5.6 Hz), 8.79 (1H, s), 11.37 (1H, s), 11.88 (1H, s).

MS (ESI) m/z: 545 (M+H⁺).

Example 133N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-propionylpiperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and propionyl chloride in a similar manner to Example 100.

Melting point: 214-228° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 0.88-1.10 (3H, m), 1.70-2.05 (2H, m), 2.06-2.60 (2H,m), 2.91 (3H, s), 3.14 (2H, br.s), 3.20-3.90 (5H, m), 3.95-4.80 (5H, m),7.09 (1H, d, J=11.0 Hz), 7.17 (1H, dd, J=8.8, 1.2 Hz), 7.41 (1H, d,J=8.8 Hz), 7.71 (1H, s), 8.20-8.50 (2H, m), 11.00-11.40 (1H, m), 11.86(1H, s).

MS (ESI) m/z: 529 (M+H⁺).

Example 134N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-isobutyrylpiperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and isobutyryl chloride in a similar manner to Example 100.

Melting point: 266-272° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 0.80-1.15 (6H, m), 1.70-2.05 (2H, m), 2.65-2.80 (1H,m), 2.90 (3H, s), 2.90-4.80 (12H, m), 7.09 (1H, d, J=11.0 Hz), 7.17 (1H,dd, J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.71 (1H, s), 8.00-8.30 (1H,m), 8.30-8.50 (1H, m), 10.95-11.50 (1H, m), 11.86 (1H, s).

MS (ESI) m/z: 543 (M+H⁺).

Example 135N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2,2-dimethylpropanoyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and pivaloyl chloride in a similar manner to Example 100.

Melting point: 250-255° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.20 (9H, s), 1.70-1.81 (1H, m), 1.90-2.00 (1H, m),2.88 (3H, s), 3.10 (2H, br.s), 3.20-3.70 (4H, m), 3.95-4.08 (1H, m),4.10-4.20 (1H, m), 4.25-4.35 (1H, m), 4.35-4.80 (3H, m), 7.10 (1H, s),7.16 (1H, dd, J=8.8, 1.9 Hz), 7.41 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=1.9Hz), 8.06 (1H, br.s), 8.38 (1H, d, J=7.8 Hz), 11.31 (1H, br.s), 11.84(1H, s).

MS (ESI) m/z: 557 (M+H⁺).

Example 136N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(3,3-dimethylbutanoyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and tert-butylacetyl chloride in a similar manner to Example 100.

Melting point: 260-265° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 0.91, 1.04 (total 9H, each s), 1.68-1.82 (1H, m),1.93-2.40 (3H, m), 2.91 (3H, s), 3.00-3.20 (2H, m), 3.20-4.80 (10H, m),7.08 (1H, s), 7.17 (1H, dd, J=8.7, 1.2 Hz), 7.41 (1H, d, J=8.7 Hz), 7.69(1H, d, J=7.6 Hz), 7.93-8.18 (1H, m), 8.38-8.45 (1H, m), 10.95-11.30(1H, m), 11.80-11.90 (1H, m).

MS (ESI) m/z: 571 (M+H⁺).

Example 137N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2,2,2-trifluoroacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and trifluoroacetic anhydride in a similar manner to Example 100.

Melting point: 262-267° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.82-1.98 (1H, m), 2.05-2.21 (1H, m), 2.89 (3H, s),3.05-3.20 (2H, m), 3.40-3.75 (4H, m), 3.85-3.95 (1H, m), 4.00-4.07 (1H,m), 4.20-4.70 (4H, m), 7.10 (1H, s), 7.18 (1H, dd, J=8.6, 1.9 Hz), 7.41(1H, d, J=8.6 Hz), 7.72 (1H, s), 8.47 (1H, dd, J=22.4, 7.9 Hz), 8.60(1H, br), 11.08 (1H, br.s), 11.87 (1H, s).

MS (ESI) m/z: 569 (M+H⁺).

Example 138N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(cyclopropylcarbonyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and cyclopropanecarbonyl chloride in a similar manner to Example100.

Melting point: 280-286° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 0.25-0.80 (4H, m), 1.65-2.15 (4H, m), 2.91 (3H, s),2.90-3.20 (3H, m), 3.35-3.70 (2H, m), 4.00-4.80 (6H, m), 7.06 (1H, s),7.18 (1H, d, J=8.8 Hz), 7.42 (1H, d, J=8.7 Hz), 7.71 (1H, s), 8.18 (1H,br.s), 8.40, 8.48 (total 1H, each br.s), 11.11 (1H, br.s), 11.85 (1H,s).

MS (ESI) m/z: 542 (M+H⁺).

Example 139N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(cyclobutylcarbonyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and cyclobutanecarbonyl chloride in a similar manner to Example 100.

Melting point: 271-275° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.60-2.30 (8H, m), 2.89 (3H, s), 3.12 (2H, br.s),3.20-3.75 (6H, m), 3.75-3.90 (1H, m), 4.05-4.80 (4H, m), 7.08 (1H, s),7.15 (1H, dd, J=9.0, 2.0 Hz), 7.39 (1H, d, J=9.0 Hz), 7.68 (1H, d, J=2.0Hz), 8.15 (1H, br.s), 8.39 (1H, br), 11.19 (1H, br.s), 11.84 (1H, s).

MS (ESI) m/z: 555 (M+H⁺).

Example 140N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(cyclopentylcarbonyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and cyclopentanecarbonyl chloride in a similar manner to Example100.

Melting point: 254-260° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.30-2.10 (10H, m), 2.90 (3H, s), 3.00-3.20 (2H, m),3.20-3.75 (5H, m), 3.80-4.80 (6H, m), 7.09 (1H, s), 7.17 (1H, dd, J=8.7,2.0 Hz), 7.42 (1H, d, J=8.7 Hz), 7.71 (1H, s), 7.95-8.30 (1H, m),8.35-8.50 (1H, m), 11.23 (1H, br.s), 11.85 (1H, s).

MS (ESI) m/z: 569 (M+H⁺).

Example 1412-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-1-yl)-2-oxoethylacetate

The title compound was obtained from the compound obtained in Example118 and acetoxyacetyl chloride in a similar manner to Example 100.

¹H-NMR (CDCl₃) δ: 1.70-2.00 (1H, m), 2.05-2.48 (3H, m), 2.51 (3H, s),2.70-3.05 (4H, m), 3.05-4.10 (5H, m), 4.20-4.48 (1H, m), 4.50-5.10 (4H,m), 6.87 (1H, br.s), 7.10-7.82 (4H, m), 7.32 (1H, d, J=8.8 Hz), 8.35(1H, br.s), 9.34, 9.45 (total 1H, each br.s).

MS (ESI) m/z: 573 (M+H⁺).

Example 142N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-glycoloylpiperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (301.8 mg) obtained in Example 141 was dissolved intetrahydrofuran (10 ml), and a 1N aqueous solution (0.53 ml) of sodiumhydroxide was added to stir the mixture at room temperature for 18hours. Water was added to the reaction mixture to conduct extractionwith methylene chloride. The resultant organic layer was successivelywashed with water and saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, the residue was purified by column chromatography onsilica gel (methylene chloride:methanol=20:1-10:1), and the solvent wasdistilled off under reduced pressure. The thus-obtained purified productwas dissolved in ethanol (3 ml) and methylene chloride (2 ml), and a 1Nethanol solution of hydrochloric acid to stir the mixture for 30minutes. The solvent was distilled off under reduced pressure, and theresidue was solidified with diethyl ether to obtain the title compound(195 mg).

Melting point: 216-230° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.70-1.80 (1H, m), 1.88-2.10 (2H, m), 2.68 (3H, s),3.18 (2H, s), 3.08-3.70 (5H, m), 3.80-3.95 (1H, m), 4.00-4.25 (3H, m),4.25-4.50 (2H, m), 4.50-4.65 (1H, m), 7.09 (1H, d, J=11.0 Hz), 7.17 (1H,dd, J=8.8, 2.0 Hz), 7.42 (1H, d, J=8.8 Hz), 7.71 (1H, s), 8.33 (1H,br.s), 8.35-8.50 (1H, m), 10.80-11.30 (1H, br.s), 11.84 (1H, br.s).

Example 143N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 in a similar manner to Example 100.

Melting point: 214-228° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s),3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82 (7H, m), 3.88-4.80 (5H, m),7.09 (1H, d, J=9.0 Hz), 7.17 (1H, dd, J=8.8, 1.9 Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, d, J=1.9 Hz), 8.29 (1H, br.s), 8.40-8.50 (1H, m), 11.34(1H, br.s), 11.86 (1H, s).

MS (ESI) m/z: 545 (M+H)⁺.

Example 144N-[(3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example122 and methoxyacetyl chloride in a similar manner to Example 100.

Melting point: 190-208° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 1.70-1.83 (1H, br), 1.85-2.10 (1H, m), 2.91 (3H, s),3.00-3.55 (10H, m), 3.62-3.85 (1H, m), 3.90-4.50 (6H, m), 4.63-4.78 (1H,br), 7.04 (1H, td, J=9.4, 2.4 Hz), 7.07-7.13 (1H, br), 7.37-7.44 (1H,m), 8.16-8.49 (2H, m), 11.30-11.70 (1H, br), 11.72-11.80 (1H, br).

MS (FAB) m/z: 529 (M+H⁺).

Example 145N-((3R*,4S*)-1-(3-{tert-butyl(diphenyl)silyl}oxy)-2,2-dimethylpropanoyl)-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

Thionyl chloride (3.0 ml) and a catalytic amount of dimethylformamidewere added to a solution of the compound (261 mg) obtained inReferential Example 158 in chloroform (10 ml), and the mixture wasstirred overnight at 60° C. The reaction mixture was concentrated underreduced pressure, giving a pale yellow oil. The title compound wasobtained from this product and the compound (200 mg) obtained in Example118 in a similar manner to Example 100.

Melting point: 153° C.

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.39 (6H, d, J=3.9 Hz), 1.57 (1H, br.s),2.26 (1H, d, J=10.7 Hz), 2.57 (3H, s), 2.86 (4H, s), 2.97-3.01 (2H, m),3.78 (4H, s), 4.20 (1H, br.s), 4.33 (1H, d, J=13 Hz), 4.42 (1H, br.s),4.67 (1H, d, J=13 Hz), 6.88 (1H, s), 7.20-7.23 (1H, m), 7.32-7.46 (7H,m), 7.64-7.65 (6H, m), 7.86 (1H, d, J=6.8 Hz), 8.23 (1H, s), 9.10 (1H,s).

Example 146N-[(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.594 ml) wasadded to a solution of the compound (241 mg) obtained in Example 145 intetrahydrofuran (30 ml) under ice cooling, and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the resultant residue was dissolved inmethylene chloride. The solution was washed with water and saturatedaqueous solution of sodium chloride and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by preparative thin-layer chromatographyon silica gel (methylene chloride:methanol=9:1) to obtain the titlecompound (116 mg).

Melting point: 220° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.17 (6H, d, J=8.3 Hz), 1.79 (1H, br.s), 1.91-1.97(1H, m), 2.49 (3H, s), 2.87 (4H, s), 3.35-3.50 (4H, m), 3.81 (1H, br.s),3.97 (1H, m), 4.10-4.15 (1H, m), 4.32 (1H, br.s), 4.42 (1H, br.s), 4.52(1H, t, J=5.7 Hz), 7.10 (1H, s), 7.16-7.19 (1H, m), 7.42 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.11 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=7.3 Hz), 11.8(1H, s).

MS (FAB) m/z: 573 (M+H⁺).

Example 147N-[(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained in Example118 and the compound obtained in Referential Example 160 in a similarmanner to Example 145.

Melting point: 240° C. (decomposed).

¹H-NMR (CDCl₃) δ: 1.34 (3H, s), 1.37 (3H, s), 1.65-1.77 (1H, m),2.33-2.37 (1H, m), 2.53 (3H, s), 2.82-3.29 (6H, m), 3.34 (3H, s), 3.41(1H, d, J=9.3 Hz), 3.56 (1H, d, J=9.3 Hz), 3.76 (2H, d, J=5.9 Hz), 4.26(1H, m), 4.44-4.53 (2H, m), 4.82 (1H, d, J=13.7 Hz), 6.88 (1H, d, J=1.5Hz), 7.20-7.23 (1H, m), 7.33 (1H, d, J=8.8 Hz), 7.64 (1H, d, J=1.5 Hz),7.90 (1H, d, J=7.1 Hz), 8.22 (1H, d, J=5.1 Hz), 9.18 (1H, s).

MS (FAB) m/z: 587 (M+H⁺).

Example 1482-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-1-yl)-1,1-dimethyl-2-oxoethylacetate

The title compound was obtained from the compound obtained in Example118 and 2-acetoxyisobutyryl chloride in a similar manner to Example 100.

Melting point: 190° C. (decomposed).

¹H-NMR (CDCl₃) δ: 1.56-1.67 (8H, m), 2.08 (3H, s), 2.35 (1H, d, J=10.5Hz), 2.52 (3H, s), 2.82-2.84 (2H, m), 2.90-2.96 (2H, m), 3.14 (1H,br.s), 3.75 (2H, s), 4.25 (1H, br.s), 4.40-4.47 (1H, m), 4.54 (1H,br.s), 4.80 (1H, br.s), 6.86 (1H, s), 7.20-7.33 (3H, m), 7.64 (1H, d,J=1.7 Hz), 7.76 (1H, d, J=7.3 Hz), 9.11 (1H, s).

MS (FAB) m/z: 601 (M+H⁺).

Example 149N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-hydroxy-2-methylpropanoyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

Sodium methoxide (76.8 mg) was added to a solution of the compound (190mg) obtained in Example 148 in methanol (50 ml), and the mixture wasstirred overnight at room temperature. After the reaction mixture wasconcentrated under reduced pressure, the resultant residue was purifiedby preparative thin-layer chromatography on silica gel (methylenechloride:methanol=9:1) to obtain the title compound (130 mg).

Melting point: 190° C. (decomposed)

¹H-NMR (CDCl₃) δ: 1.53 (3H, s), 1.56-1.78 (5H, m), 2.34 (1H, d, J=10.5Hz), 2.53 (3H, s), 2.83-2.86 (2H, m), 2.91-2.93 (2H, m), 3.30 (1H, d,J=12.5 Hz), 3.75 (2H, s), 4.28 (1H, d, J=5.6 Hz), 4.43 (1H, s), 4.65(1H, d, J=13.5 Hz), 4.95 (1H, d, J=13.5 Hz), 6.92 (1H, d, J=1.5 Hz),7.20-7.23 (1H, m), 7.33 (1H, d, J=8.6 Hz), 7.65 (1H, d, J=2.0 Hz), 8.43(1H, d, J=5.6 Hz), 9.14 (1H, s).

MS (FAB) m/z: 559 (M+H⁺).

Example 150N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(3-hydroxycyclobutyl)carbonyl]piperidin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (306 mg) obtained in Example 118, n-methylmorpholine (200μl), 1-hydroxybenzotriazole monohydrate (87 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg)were added to a solution of the compound (117 mg) obtained ReferentialExample 152 in a mixed solvent of tetrahydrofuran (20 ml), methylenechloride (3.0 ml) and N,N-dimethylformamide (2.0 ml), and the mixturewas stirred at room temperature for 3 days. The reaction mixture wasdiluted with methylene chloride, and a saturated aqueous solution ofsodium hydrogencarbonate was added to separate the mixture into twolayers. The resultant organic layer was washed with saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate andthen concentrated under reduced pressure. The resultant residue waspurified by column chromatography on silica gel (methylenechloride:methanol=10:1) to obtain a free base (207 mg) of the titlecompound. The free base was treated with a 1N ethanol solution ofhydrochloric acid to obtain the title compound.

Melting point: 200° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.78-2.10 (4H, m), 2.24-2.68 (3H, m), 2.75-5.20(14H, m), 2.91 (3H, s), 7.08 (0.5H, s), 7.09 (0.5H, s), 7.18 (1H, dd,J=8.8, 2.0 Hz), 7.42 (1H, d, J=8.8 Hz), 7.70 (1H, d, J=2.0 Hz),8.05-8.28 (1H, br), 8.38 (0.5H, br.d, J=7.3 Hz), 8.43 (0.5H, br.d, J=8.3Hz), 10.80-11.25 (1H, br), 11.84 (1H, br.s).

MS (ESI) m/z: 571 (M+H⁺).

Example 151N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(methoxycyclobutyl)carbonyl]piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and the compound obtained in Referential Example 154 in a similarmanner to Example 150.

Melting point: 191° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.69-2.23 (4H, m), 2.25-2.40 (1H, m), 2.71-2.84(0.5H, m), 2.89-3.93 (9.5H, m), 2.91 (3H, s), 3.01 (1H, s), 3.14 (2H,s), 4.05-4.80 (5H, m), 7.09 (1H, s), 7.18 (1H, d, J=8.4 Hz), 7.42 (1H,d, J=8.4 Hz), 7.70 (1H, s), 8.00-8.30 (1H, br), 8.36-8.53 (1H, m),11.25-11.75 (1H, br), 11.85 (1H, br.s).

MS (ESI) m/z: 585 (M+H⁺).

Example 152N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[3-methoxy-2-(methoxymethyl)propanoyl]piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by condensing a carboxylic acid obtainedby hydrolysis of the compound obtained in Referential Example 155 withthe compound obtained in Example 118 in a similar manner to Example 150.

Melting point: 178-184° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.69-1.82 (1H, m), 1.84-2.04 (1H, m), 2.91 (3H, s),3.00-3.75 (17H, m), 3.95-4.55 (5H, m), 4.60-4.80 (1H, m), 7.10 (1H,br.s), 7.18 (1H, dd, J=8.8, 2.0 Hz), 7.42 (1H, d, J=8.8 Hz), 7.69 (0.5H,br.s), 7.71 (1H, br.s), 8.18-8.28 (1H, br), 8.35-8.50 (1H, br), 11.83(1H, br.s).

MS (ESI) m/z: 603 (M+H⁺).

Example 153N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and the compound obtained in Referential Example 156 in a similarmanner to Example 150.

Melting point: 225-248° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.55-1.68 (4H, m), 1.70-1.85 (1H, m), 1.85-2.05 (1H,m), 2.60-2.95 (1H, m), 2.89 (3H, s), 2.95-3.20 (3H, m), 3.20-4.00 (9H,m), 4.00-4.80 (4H, m), 7.08 (1H, s), 7.17 (1H, dd, J=8.8, 2.0 Hz), 7.42(1H, d, J=8.8 Hz), 7.71 (1H, s), 8.00-8.30 (1H, m), 8.35-8.50 (1H, m),11.16 (1H, br.s), 11.85 (1H, s).

MS (ESI) m/z: 585 (M+H⁺).

Example 154N-((3R*,4S*)-1-benzoyl-4-{[(5-Chloroindol-2-yl)carbonyl]amino}piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and benzoyl chloride in a similar manner to Example 100.

Melting point: 215-225° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.75-1.90 (1H, m), 1.90-2.20 (1H, m), 2.93 (3H, s),3.10-4.00 (8H, m), 4.05-4.80 (4H, m), 7.00-7.60 (5H, m), 7.08 (1H, s),7.16 (1H, dd, J=8.8, 1.6 Hz), 7.40 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=1.6Hz), 8.31 (1H, br.s), 8.46 (1H, br.s), 11.39 (1H, br.s), 11.86 (1H, s).

MS (FAB) m/z: 577 (M+H⁺).

Example 155 tert-Butyl(3R*,4S*)-3-({[5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl]carbonyl}amino)-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 207 and the compound obtained in Referential Example42 in a similar manner to Example 91.

¹H-NMR (DMSO-d₆) δ: 1.00 (9H, s), 1.12 (6H, s), 1.15-1.50 (9H, m),1.63-1.75 (1H, m), 1.82-2.00 (1H, m), 2.60-2.80 (3H, m), 2.83-2.95 (2H,m), 3.12-3.30 (1H, m) 3.30 (2H, s) 3.58 (2H, s), 3.85-4.10 (2H, m), 4.19(1H, br.s), 4.37 (1H, br.s), 7.04 (1H, s), 7.16 (1H, d, J=9.0 Hz),7.30-7.50 (7H, m), 7.50-7.65 (4H, m), 7.70 (1H, s), 7.99 (1H, d, J=6.8Hz), 8.45 (1H, br.s), 11.82 (1H, s).

MS (ESI) m/z: 869 (M+H)⁺

Example 1565-(2-{[tert-Butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-N-((3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidedihydrochloride

The title compound was obtained by treating the compound obtained inExample 155 in a similar manner to Example 95.

¹H-NMR (DMSO-d₆) δ: 1.04 (9H, s), 1.43, 1.48 (total 6H, each s),1.85-2.00 (1H, m), 2.05-2.20 (1H, m), 2.95-3.20 (2H, m), 3.25-3.60 (6H,m), 3.80-3.90 (1H, m), 3.95-4.05 (1H, m), 4.45-4.55 (1H, m), 4.60-4.85(3H, m), 7.10-7.20 (2H, m), 7.35-7.55 (7H, m), 7.55-7.75 (5H, m), 8.52(1H, dd, J=14.4, 7.8 Hz), 8.93 (1H, br), 9.20-9.40 (2H, m), 11.30-11.50(1H, m), 11.87, 11.92 (total 1H, each s).

MS (ESI) m/z: 769 (M+H⁺).

Example 1575-(2-{[tert-Butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-N-[(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide

The title compound was obtained from the compound obtained in Example156 and methoxyacetyl chloride in a similar manner to Example 100.

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.20 (6H, s), 1.60-1.85 (1H, m),2.25-2.40 (1H, m), 2.36 (2H, s), 2.70-3.20 (4H, m), 3.20-3.55 (4H, m),3.55-3.70 (2H, m), 3.95-4.10 (3H, m), 4.10-4.90 (4H, m), 6.90 (1H, d,J=1.5 Hz), 7.15-7.30 (2H, m), 7.30-7.50 (6H, m), 7.60-7.70 (5H, m),8.15-8.22 (1H, m), 8.46 (1H, d, J=5.1 Hz), 9.28 (1H, s).

MS (ESI) m/z: 842 (M+H⁺).

Example 158N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-5-(2-hydroxy-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example157 in a similar manner to Example 146.

Melting point: 221-232° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.32 (3H, s), 1.40 (3H, s), 1.70-1.85 (1H, m),1.85-2.10 (1H, m), 2.60-3.35 (8H, m), 3.40-3.82 (3H, m), 3.85-4.05 (3H,m), 4.05-4.35 (2H, m), 4.50-4.60 (1H, m), 4.55-4.80 (2H, m), 5.75-5.85(1H, m), 7.08 (1H, br.s), 7.17 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.20-8.35 (1H, m), 8.40-8.55 (1H, m), 10.00-10.35(1H, m), 11.87 (1H, s).

MS (ESI) m/z: 603 (M+H⁺).

Example 159 tert-Butyl(3R*,4S*)-4-{[(5-fluoroindol-2-yl)carbonyl]amino}-3-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylate

The title compound was obtained from the compound obtained inReferential Example 209 and the compound obtained in Referential Example148 in a similar manner to Example 91.

¹H-NMR (CDCl₃) δ: 1.16 (6H, d, J=6.6 Hz), 1.53 (9H, s), 1.65-1.80 (1H,m), 2.23-2.32 (1H, m), 2.80-3.10 (6H, m), 3.10-3.25 (1H, m), 3.80-3.90(2H, m), 4.00-4.50 (4H, m), 6.91 (1H, s), 6.95-7.05 (1H, m), 7.25-7.40(2H, m), 7.74 (1H, br.s), 8.21 (1H, br.s), 9.30 (1H, s).

MS (ESI) m/z: 585 (M+H⁺).

Example 160N-((3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-isopropyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamidedihydrochloride

The title compound was obtained by treating the compound obtained inExample 159 in a similar manner to Example 95.

¹H-NMR (DMSO-d₆) δ: 1.28-1.40 (6H, m), 1.85-2.00 (1H, m), 2.05-2.20 (1H,m), 2.40-2.60 (1H, m), 2.95-3.90 (8H, m), 4.40-4.55 (2H, m), 4.60-4.75(2H, m), 7.00-7.20 (2H, m), 7.30-7.50 (2H, m), 8.45-8.60 (1H, m),8.85-9.05 (1H, m), 9.05-9.50 (2H, m), 11.60-11.90 (2H, m).

MS (ESI) m/z: 485 (M+H⁺).

Example 161N-[(3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example160 and methoxyacetyl chloride in a similar manner to Example 100.

Melting point: 214-228° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.25-1.40 (6H, m), 1.68-1.82 (1H, m), 1.85-2.10 (1H,m), 2.90-3.60 (8H, m), 3.60-3.85 (2H, m), 3.85-4.40 (5H, m), 4.40-4.55(2H, m), 4.60-4.75 (1H, m), 7.00-7.15 (2H, m), 7.35-7.50 (2H, m),8.15-8.50 (2H, m), 10.80-11.30 (1H, m), 11.73 (1H, d, J=6.6 Hz).

MS (ESI) m/z: 557 (M+H⁺).

Example 162N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(dimethylamino)carbonyl]piperidin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and N,N-dimethylcarbamoyl chloride in a similar manner to Example100.

Melting point: 267-270° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.65-1.78 (1H, m), 1.97-2.10 (1H, m), 2.70 (6H, s),2.90 (3H, s), 2.95-3.80 (8H, m), 4.25-4.80 (4H, m), 7.08 (1H, s), 7.16(1H, dd, J=8.8, 1.8 Hz), 7.41 (1H, d, J=8.8 Hz), 7.70 (1H, s), 8.31 (1H,br.s), 8.40 (1H, d, J=7.3 Hz), 11.15-11.60 (1H, m), 11.82 (1H, s).

MS (ESI) m/z: 544 (M+H⁺).

Example 163N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(ethylamino)carbonyl]piperidin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and ethyl isocyanate in a similar manner to Example 100.

Melting point: 221-235° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 0.98 (3H, t, J=7.1 Hz), 1.60-1.70 (1H, m), 1.80-1.95(1H, m), 2.90 (3H, s), 2.95-3.40 (6H, m), 3.40-4.00 (4H, m), 4.25-4.80(4H, m), 6.60-6.80 (1H, m), 7.09 (1H, s), 7.16 (1H, dd, J=8.8, 1.9 Hz),7.41 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=1.9 Hz), 8.02 (1H, br.s), 8.35(1H, d, J=7.1 Hz), 11.20-11.70 (1H, m), 11.82 (1H, s).

MS (FAB) m/z: 544 (M+H⁺).

Example 164N-((3R*,4S*)-1-[(tert-Butylamino)carbonyl]-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example118 and tert-butyl isocyanate in a similar manner to Example 100.

Melting point: 236-238° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.21 (9H, s), 1.60-1.70 (1H, m), 1.80-1.90 (1H, m),2.87 (3H, s), 3.00-3.40 (6H, m), 3.49 (1H, br.s), 3.80-3.90 (1H, m),3.90-4.00 (1H, m), 4.20-4.35 (2H, m), 4.47 (1H, br.s), 5.90 (1H, s),7.06 (1H, s), 7.16 (1H, dd, J=8.8, 1.9 Hz), 7.41 (1H, d, J=8.8 Hz), 7.67(1H, d, J=1.9 Hz), 8.04 (1H, d, J=6.8 Hz), 8.34 (1H, d, J=7.3 Hz), 11.22(1H, br.s), 11.79 (1H, s).

MS (FAB) m/z: 572 (M+H⁺).

Example 165 Methyl2-((3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-3-yl)acetatedihydrochloride

The title compound was obtained from the compound obtained in Example118 and methyl bromoacetate in a similar manner to Example 102.

Melting point: 253-255° C. (decomposed).

¹H-NMR (DMSO-d₆, 80° C.) δ: 1.95-2.10 (1H, m), 2.10-2.25 (1H, m), 2.88(3H, s), 3.00-3.73 (8H, m), 3.75 (3H, s), 3.97-4.15 (2H, m), 4.30-4.80(4H, m), 7.08-7.20 (2H, m), 7.44 (1H, d, J=8.6 Hz), 7.63 (1H, d, J=2.0Hz), 8.42 (1H, d, J=7.3 Hz), 8.62 (1H, br.s), 11.82 (1H, br.s).

MS (ESI) m/z: 545 (M+H⁺).

Example 1662-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}piperidin-3-yl)aceticacid hydrochloride

The title compound was obtained by treating the compound obtained inExample 165 in a similar manner to Example 101.

Melting point: 234-240° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.75-1.95 (1H, m), 2.05-2.20 (1H, m), 2.88 (3H, s),2.95-3.90 (10H, m), 4.20-4.70 (4H, m), 7.11 (1H, s), 7.16 (1H, dd,J=8.8, 2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=2.0 Hz), 8.46(1H, br.d, J=7.8 Hz), 8.65 (1H, br.s), 11.60-12.70 (2H, br.s), 11.91(1H, br.s).

Example 167N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyethyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidedihydrochloride

The title compound was obtained from the compound obtained in Example118 and 2-bromoethyl methyl ether in a similar manner to Example 102(NMR was measured in the form of a free base).

Melting point: 238-242° C. (decomposed).

¹H-NMR (CDCl₃) δ: 1.75-1.83 (2H, m), 2.27-2.39 (2H, m), 2.52 (3H, s),2.60-2.66 (1H, m), 2.69-2.75 (1H, m), 2.81-2.90 (2H, m), 2.96-3.07 (2H,m), 3.41 (3H, s), 3.53-3.60 (2H, m), 3.75 (each 1H, AB type d, J=15.5Hz), 4.02-4.05 (1H, m), 4.40 (1H, br), 6.88 (1H, d, J=1.5 Hz), 7.18-7.21(1H, m), 7.31-7.33 (1H, m), 7.63 (1H, d, J=1.5 Hz), 8.17 (1H, d, J=5.0Hz), 8.26 (1H, d, J=7.0 Hz), 9.30 (1H, br.s).

MS (FAB) m/z: 531 (M+H⁺).

Example 168N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-fluoroethyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidedihydrochloride

The title compound was obtained from the compound obtained in Example118 and 2-fluoroethyl bromide in a similar manner to Example 102 (NMRwas measured in the form of a free base).

Melting point: 228-233° C. (decomposed).

¹H-NMR (CDCl₃) δ: 1.77 (2H, dq, J=12.5, 4.0 Hz), 2.28-2.32 (1H, m), 2.41(1H, t, J=12.5 Hz), 2.52 (3H, s), 2.65 (1H, d, J=10.5 Hz), 2.76-2.81(1H, m), 2.83-2.86 (3H, m), 2.98-3.05 (3H, m), 3.75 (each 1H, AB type d,J=15.5 Hz), 4.02-4.08 (1H, m), 4.45 (1H, br), 4.54-4.59 (1H, m),4.64-4.70 (1H, m), 6.87 (1H, d, J=1.5 Hz), 7.19-7.22 (1H, m), 7.32 (1H,d, J=8.5 Hz), 7.64 (1H, d, J=2.0 Hz), 8.11 (1H, d, J=5.5 Hz), 8.20 (1H,d, J=7.3 Hz), 9.30 (1H, br).

MS (FAB) m/z: 519 (M+H⁺).

Example 169N-((3R,4S)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A 4N dioxane solution (7.0 ml) of hydrochloric acid was added to adioxane solution (15 ml) of the compound (630 mg) obtained inReferential Example 214, and the mixture was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated under reducedpressure. The thus-obtained yellow solids (590 mg) and the compound (379mg) obtained in Referential Example 10 were used to obtain a free base(330 mg) of the title compound in a similar manner to Example 91. Thisfree base was treated with an ethanol solution of hydrochloric acid toobtain the title compound (NMR was measured in the form of a free base).

Melting point: 202-222° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.65-1.85 (1H, m), 1.87, 2.06 (total 3H, each s),1.88-2.10 (1H, m), 2.37 (3H, s), 2.65-2.77 (2H, m), 2.79-2.89 (2H, m),2.99-3.09 (0.5H, m), 3.30-3.52 (2H, m), 3.64 (2H, s), 3.70-3.80 (0.5H,m), 3.96-4.21 (2H, m), 4.27 (1H, br.s), 4.35-4.48 (1H, m), 7.07, 7.11(total 1H, each s), 7.18 (1H, d, J=8.8 Hz), 7.42 (1H, d, J=8.8 Hz), 7.71(1H, s), 8.16-8.22 (1H, m), 8.37, 8.46 (total 1H, each d, J=7.8 Hz),11.81, 11.83 (total 1H, each s).

MS (ESI) m/z: 515 (M+H⁺).

[α]²⁵ _(D)=−56.0° (c=0.50, methanol).

Example 170N-((3R,4R)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 219 and Referential Example 10 in a similar mannerto Example 169.

Melting point: 221-238° C.

¹H-NMR (DMSO-d₆) δ: 1.45-1.56 (0.5H, m), 1.60-1.70 (0.5H, m), 1.89-2.01(1H, m), 2.05 (3H, s), 2.51-2.67 (1H, m), 2.88 (3H, s), 3.00-3.22 (3H,m), 3.31-3.40 (3H, m), 3.56-3.67 (0.5H, m), 3.78-4.02 (1.5H, m),4.22-4.44 (2H, m), 4.56-4.72 (1H, m), 7.02 (1H, s), 7.15 (1H, dd, J=8.8,2.0 Hz), 7.37 (1H, d, J=8.8 Hz), 7.67 (1H, d, J=2.0 Hz), 8.42 (1H, d,J=9.8 Hz), 8.67-8.78 (1H, m), 11.02-11.14 (1H, m), 11.72 (0.5H, s),11.74 (0.5H, s).

MS (FAB) m/z: 515 (M+H⁺).

[α]²⁵ _(D)=−105.4° (c=0.58, methanol).

Example 171N-[(3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 221 in a similar manner to Example 169.

Melting point: 207-220° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s),3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82 (7H, m), 3.88-4.80 (5H, m),7.09 (1H, d, J=9.0 Hz), 7.17 (1H, dd, J=8.8, 1.9 Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, d, J=1.9 Hz), 8.29 (1H, br.s), 8.40-8.50 (1H, m),11.20-11.50 (1H, m), 11.85 (1H, s).

MS (ESI) m/z: 545 (M+H⁺).

[α]²⁵ _(D)=−53.4° (c=0.52, methanol).

Example 172N-[(3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 223 in a similar manner to Example 169.

Melting point: 213-230° C.

¹H-NMR (DMSO-d₆) δ: 1.45-1.56 (0.5H, m), 1.61-1.70 (0.5H, m), 1.89-2.00(1H, m), 2.05 (3H, s), 2.45-2.67 (1H, m), 2.88 (3H, s), 3.00-3.21 (4H,m), 3.32-3.56 (7H, m), 3.78-3.89 (2H, m), 4.00-4.24 (2H, m), 4.26-4.43(2H, m), 7.02 (1H, s), 7.13 (1H, dd, J=8.8, 2.0 Hz), 7.37 (1H, d, J=8.8Hz), 7.67 (1H, d, J=2.0 Hz), 8.41 (1H, d, J=9.8 Hz), 8.74 (1H, d, J=9.8Hz), 10.80-10.90 (1H, m), 11.72 (1H, s).

MS (FAB) m/z: 545 (M+H⁺).

[α]²⁵ _(D)=−100.3° (c=0.51, methanol).

Example 173N-((3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the low-polar compound obtained inReferential Example 176 and the compound obtained in Referential Example10 in a similar manner to Example 169.

¹H-NMR (DMSO-d₆) δ: 2.41-2.56 (2H, m), 2.91 (3H, s), 3.01-3.23 (1H, m),3.24-3.56 (5H, m), 3.62-3.67 (1H, m), 4.21-4.44 (1H, m), 4.56-4.78 (2H,m), 7.11 (1H, s), 7.16 (1H, dd, J=8.8, 2.0 Hz), 7.22 (1H, d, J=8.5 Hz),7.41 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.0 Hz), 8.40-8.50 (1H, m),11.34-11.56 (1H, m), 11.82 (1H, s).

MS (FAB) m/z: 488 (M+H⁺).

Example 174N-((3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the high-polar compound obtained inReferential Example 176 and the compound obtained in Referential Example10 in a similar manner to Example 169.

¹H-NMR (DMSO-d₆) δ: 2.41-2.56 (2H, m), 2.91 (3H, s), 3.23-3.41 (2H, m),3.43-3.50 (2H, m), 3.56-3.67 (2H, m), 4.37 (1H, dd, J=13.9, 7.1 Hz),4.40-4.50 (1H, m), 4.56-4.78 (2H, m), 7.12 (1H, s), 7.17 (1H, dd, J=8.8,2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=2.0 Hz), 8.44 (1H, d,J=8.5 Hz), 8.15 (1H, d, J=8.5 Hz), 11.42-11.53 (1H, m), 11.79 (1H, s).

MS (FAB) m/z: 488 (M+H⁺).

Example 175 Ethyl(3R,4S)-5-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}valerate

The title compound was obtained from the compound obtained inReferential Example 225 in a similar manner to Example 169.

¹H-NMR (CDCl₃) δ: 1.09 (9H, s), 1.21 (3H, t, J=7.4 Hz), 2.49 (3H, s),2.65 (1H, dd, J=15.9, 5.4 Hz), 2.67-2.90 (5H, m), 3.60 (1H, d, J=14.9Hz), 3.72 (1H, d, J=14.9 Hz), 3.78-3.91 (2H, m), 4.00-4.21 (2H, m),4.43-4.50 (1H, m), 4.78-4.89 (1H, m), 6.81 (1H, s), 7.20 (1H, dd, J=8.8,2.0 Hz), 7.32-7.52 (m, 7H), 7.63-7.74 (6H, m), 7.89-8.01 (1H, m), 9.18(1H, s).

Example 176 Ethyl(3R,4S)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-5-hydroxy-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}valerate

After hydrogen fluoride-pyridine (0.4 ml) was added dropwise to amixture solution composed of the compound (0.54 g) obtained in Example175, pyridine (4.0 ml) and tetrahydrofuran (10 ml) under ice cooling,the reaction mixture was stirred for 18 hours while the temperaturethereof was gradually raised to room temperature. The reaction mixturewas concentrated, and the resultant residue was purified by columnchromatography on silica gel (chloroform:methanol=9:1) to obtain thetitle compound (0.31 g).

¹H-NMR (CDCl₃) δ: 1.20 (3H, t, J=7.4 Hz), 2.49 (3H, s), 2.67-2.90 (6H,m), 3.62-3.74 (3H, m), 3.78-3.94 (1H, m), 4.00-4.20 (2H, m), 4.30-4.40(1H, m), 4.80-4.89 (1H, m), 6.93 (1H, s), 7.23 (1H, dd, J=8.8, 2.0 Hz),7.33 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=8.5 Hz), 7.61 (1H, d, J=2.0 Hz),7.88 (1H, d, J=8.5 Hz), 9.29 (1H, s).

Example 177N-((3S,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyran-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A 4N dioxane solution (20 ml) of hydrochloric acid was added to thecompound (0.31 g) obtained in Example 176, and the mixture was heatedunder reflux for 4 hours. The reaction mixture was concentrated, and theresultant residue was recrystallized from diethyl ether to obtain thetitle compound (0.23 g).

Melting point: 221-238° C. (decomposed).

¹H-NMR and MS (FAB): The same as those of the enantiomer in Example 174.

Example 178N-((3R*,4R*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A free base of the title compound was obtained from the compoundobtained in Referential Example 227 and 5-chloroindole-2-carboxylic acidin a similar manner to Example 91. This free base was treated with anethanol solution of hydrochloric acid to obtain the title compound.

Melting point: 241-244° C.

¹H-NMR (DMSO-d₆) δ: 2.14 (1H, br), 2.30-2.34 (1H, m), 2.92 (3H, s),3.10-3.18 (2H, m), 3.41 (4H, br), 3.68 (2H, br), 4.44 (1H, br),4.63-4.78 (3H, m), 7.16-7.18 (1H, m), 7.21 (1H, s), 7.43 (1H, d, J=8.5Hz), 7.67 (1H, d, J=4.6 Hz), 8.39 (1H, br), 8.94 (1H, br), 11.82 (1H,br).

MS (ESI) m/z: 522 (M+H⁺).

Example 179N-((3R*,4R*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A free base of the title compound was obtained from the compoundobtained in Referential Example 227 and 5-fluoroindole-2-carboxylic acidin a similar manner to Example 91. This free base was treated with anethanol solution of hydrochloric acid to obtain the title compound.

Melting point: 243-245° C.

¹H-NMR (DMSO-d₆) δ: 2.14 (1H, br), 2.30-2.33 (1H, m), 2.92 (3H, s), 3.13(2H, br), 3.51 (4H, br), 3.63 (2H, br), 4.63 (3H, br), 4.78 (1H, br),7.01-7.05 (1H, m), 7.21 (1H, s), 7.37-7.44 (2H, m), 8.36 (1H, br), 8.93(1H, d, J=6.8 Hz), 11.72 (1H, br).

MS (ESI) m/z: 506 (M+H⁺).

Example 180N-((3R*,4R*)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-4-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A free base of the title compound was obtained from the compoundobtained in Referential Example 229 and the compound obtained inReferential Example 10 in a similar manner to Example 91. This free basewas treated with an ethanol solution of hydrochloric acid to obtain thetitle compound.

Melting point: 242-247° C.

¹H-NMR (DMSO-d₆) δ: 2.16 (1H, br), 2.45 (1H, br), 2.93 (3H, s), 3.13(2H, br), 3.26 (4H, br), 3.69 (2H, br), 4.45 (1H, br), 4.65-4.77 (3H,m), 7.01 (1H, s), 7.17 (1H, dd, J=8.7, 1.4 Hz), 7.43 (1H, d, J=8.5 Hz),7.69 (1H, s), 8.35-8.40 (1H, m), 9.04 (1H, br), 11.86 (1H, s).

MS (ESI) m/z: 522 (M+H⁺).

Example 181N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A free base of the title compound was obtained from the compoundobtained in Referential Example 231 and 5-chloroindole-2-carboxylic acidin a similar manner to Example 91. This free base was treated with anethanol solution of hydrochloric acid to obtain the title compound.

Melting point: 244-249° C.

¹H-NMR (DMSO-d₆) δ: 2.17-2.27 (2H, m), 2.90 (3H, s), 3.09 (1H, br),3.18-3.21 (2H, m), 3.31-3.34 (2H, m), 3.60-3.67 (3H, m), 4.41-4.49 (2H,m), 4.54-4.59 (2H, m), 7.04 (1H, s), 7.09-7.13 (1H, m), 7.39 (1H, d,J=8.5 Hz), 7.61 (1H, d, J=9.9 Hz), 8.52-8.56 (1H, m), 8.83-8.85 (1H, m),11.65 (1H, d, J=11.9 Hz).

MS (ESI) m/z: 522 (M+H⁺).

Example 182N-((3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A free base of the title compound was obtained from the compoundobtained in Referential Example 231 and 5-fluoroindole-2-carboxylic acidin a similar manner to Example 91. This free base was treated with anethanol solution of hydrochloric acid to obtain the title compound.

Melting point: 236-241° C.

¹H-NMR (DMSO-d₆) δ: 2.20-2.24 (2H, m), 2.89 (3H, s), 3.07 (1H, br),3.19-3.22 (2H, m), 3.60-3.66 (4H, m), 4.43-4.58 (5H, m), 6.95-7.00 (1H,m), 7.04 (1H, s), 7.32-7.38 (2H, m), 8.50 (1H, d, J=8.5 Hz), 8.83 (1H,d, J=8.5 Hz), 11.59 (1H, s).

MS (ESI) m/z: 506 (M+H⁺).

Example 183N-((3R*,4R*)-3-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-4-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

A free base of the title compound was obtained from the compoundobtained in Referential Example 233 and the compound obtained inReferential Example 10 in a similar manner to Example 91. This free basewas treated with an ethanol solution of hydrochloric acid to obtain thetitle compound.

Melting point: 244-249° C.

¹H-NMR (DMSO-d₆) δ: 2.12-2.18 (1H, m), 2.50 (1H, br), 2.92 (3H, s), 3.17(3H, br), 3.50-3.61 (5H, m), 4.45 (1H, br), 4.62-4.78 (3H, m), 6.98-7.03(2H, m), 7.36-7.42 (2H, m), 8.30 (1H, br), 9.00 (1H, d, J=8.0 Hz), 11.74(1H, s).

MS (ESI) m/z: 506 (M+H⁺).

Example 184N-((3S,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-6-oxopiperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(low-polar compound) andN-((3R,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-6-oxopiperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(high-polar compound)

The title compound was obtained from the compound obtained inReferential Example 236 and the compound obtained in Referential Example10 in a similar manner to Example 169.

Low-Polar Compound:

Melting point: 189-203° C. (decomposed).

¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.59 (1H, q, J=8.8 Hz), 2.71-2.78 (2H,m), 2.89-3.00 (2H, m), 3.03 (3H, s), 3.12 (1H, dd, J=17.6, 5.4 Hz), 3.43(1H, dd, J=12.7, 5.1 Hz), 3.70 (1H, d, J=15.2 Hz), 3.77 (1H, d, J=15.2Hz), 3.83 (1H, dd, J=12.7, 3.9 Hz), 4.55-4.67 (2H, m), 6.99 (1H, s),7.23 (1H, dd, J=8.8, 2.0 Hz), 7.33 (1H, d, J=8.8 Hz), 7.65 (1H, d, J=2.0Hz), 8.07 (1H, d, J=5.1 Hz), 8.16 (1H, d, J=5.4 Hz), 9.43 (1H, s).

MS (FAB) m/z: 501 (M+H⁺).

High-Polar Compound:

Melting point: 183-195° C. (decomposed).

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.41-2.50 (1H, m), 2.62-2.73 (3H, m),2.75-2.81 (1H, m), 2.82 (3H, s), 3.21-3.32 (2H, m), 3.34-3.50 (2H, m),3.55 (1H, d, J=15.4 Hz), 3.63 (1H, d, J=15.4 Hz), 4.30-4.40 (0.5H, m),4.50-4.60 (0.5H, m), 7.04 (1H, s), 7.15 (1H, dd, J=8.8, 2.0 Hz), 7.38(1H, d, J=8.8 Hz), 7.67 (1H, d, J=2.0 Hz), 8.49 (1H, d, J=8.5 Hz), 8.71(1H, d, J=8.5 Hz), 11.74 (1H, s).

MS (FAB) m/z: 501 (M+H⁺).

Example 1855-Chloro-N-((1R*,2S*)-2-{[4-(pyridin-4-yl)benzoyl]amino}cyclohexyl)indole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example237 in a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.40-1.52 (2H, m), 1.60-1.80 (4H, m), 1.96-2.10 (2H,m), 4.24-4.39 (2H, m), 7.15 (1H, dd, J=8.8, 2.0 Hz), 7.21 (1H, s), 7.40(1H, d, J=8.8 Hz), 7.64 (1H, d, J=2.0 Hz), 8.06 (4H, s), 8.18 (1H, J=7.3Hz), 8.34-8.42 (3H, m), 8.94 (2H, d, J=6.9 Hz), 11.91 (1H, s).

MS (FAB) m/z: 473 (M+H)⁺.

Example 1864-(4-{[((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}phenyl)pyridineN-oxide

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example240 in a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.40-1.52 (2H, m), 1.60-1.80 (4H, m), 1.88-2.00 (2H,m), 4.21-4.36 (2H, m), 7.12-7.18 (2H, m), 7.41 (1H, d, J=8.6 Hz), 7.66(1H, s), 7.80-7.87 (4H, m), 7.91 (2H, d, J=8.3 Hz), 8.01 (1H, d, J=7.6Hz), 8.09 (1H, d, J=7.3 Hz), 8.27 (2H, d, J=6.6 Hz), 11.79 (1H, s).

MS (FAB) m/z: 489 (M+H)⁺.

Example 1875-Chloro-N-((1R*,2S*)-2-{[4-(pyridin-2-yl)benzoyl]amino}cyclohexyl)indole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 71 and 4-(2-pyridyl)benzoic acid (Japanese PatentApplication Laid-Open No. 2000-119253) in a similar manner to theprocess described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.39-1.51 (2H, m), 1.60-1.80 (4H, m), 1.89-2.00 (2H,m), 4.24-4.38 (2H, m), 7.12-7.16 (2H, m), 7.36-7.39 (1H, m), 7.42 (1H,d, J=8.8 Hz), 7.66 (1H, d, J=2.0 Hz), 7.87-7.90 (1H, m), 7.92 (2H, d,J=8.3 Hz), 7.98-8.11 (3H, m), 8.15 (2H, d, J=8.3 Hz), 8.69 (1H, d, J=4.6Hz), 11.80 (1H, s).

MS (FAB) m/z: 473 (M+H)⁺.

Example 1882-(4-{[((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}phenyl)pyridineN-oxide

The title compound was obtained from the compound obtained inReferential Example 71 and the compound obtained in Referential Example241 in a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.39-1.51 (2H, m), 1.60-1.79 (4H, m), 1.89-2.00 (2H,m), 4.23-4.37 (2H, m), 7.12-7.17 (2H, m), 7.39-7.43 (3H, m), 7.61-7.64(1H, m), 7.67 (1H, d, J=2.0 Hz), 7.89 (4H, s), 8.00-8.06 (1H. m),8.08-8.02 (1H, m), 8.32-8.35 (1H, m), 11.79 (1H, s).

MS (FAB) m/z: 489 (M+H)⁺.

Example 1895-Chloro-N-[(1R*,2R*)-2-({[5-(4-pyridin-2-yl)thiazol-2-yl]carbonyl}amino)cyclohexyl]indole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 69 and lithium 5-(4-pyridyl)thiazole-2-carboxylate(Japanese Patent Application Laid-Open No. 2000-143623) in a similarmanner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.44 (2H, br.s), 1.65 (4H, br.s), 1.85-2.06 (2H, m),4.23 (1H, br.s), 4.30 (1H, br.s), 7.14-7.23 (2H, m), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.04-8.13 (2H, m), 8.13 (1H, d, J=8.8 Hz), 8.59 (1H,d, J=8.0 Hz), 8.75-8.87 (3H, m), 11.83 (1H, s).

MS (ESI) m/z: 480 (M+H)⁺.

Example 1905-Chloro-N-[(1R*,2S*)-2-({[1-(pyridin-4-yl)piperidin-4-yl]carbonyl}amino)cyclohexyl]indole-2-carboxamidehydrochloride

1-(4-Pyridyl)piperidine-4-carboxylic acid (Tetrahedron, 1998, Vol. 44,p. 7095) (206 mg) was suspended in methylene chloride (50 ml), andthionyl chloride (144 μl) was added under ice cooling to stir themixture for 30 minutes. After triethylamine (969 μl) was added to thereaction mixture, the compound (328 mg) obtained in Referential Example71 was added to stir the mixture at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, water wasadded to the residue, the mixture was concentrated under reducedpressure, and precipitate deposited was collected by filtration toobtain the title compound (310 mg).

¹H-NMR (DMSO-d₆) δ: 1.30-2.00 (10H, m), 2.74 (1H, br.s), 3.18 (2H, q,J=12.3 Hz), 4.03 (1H, br.s), 4.10-4.25 (3H, m), 7.15-7.55 (4H, m), 7.42(1H, d, J=8.8 Hz), 7.65 (1H, s), 7.91 (1H, d, J=8.8 Hz), 8.20-8.35 (3H,m), 11.91 (1H, s), 13.47 (1H, br.s).

MS (FAB) m/z: 480 (M+H)⁺.

Example 191N¹-(4-Chlorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (288 mg) obtained in Referential Example 242 was dissolvedin tetrahydrofuran (8.0 ml), lithium hydroxide (46 mg) and water (1.0ml) were successively added, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure to obtain a crude product (292 mg) of lithium2-(4-chloroanilino)-2-oxoacetate as a colorless solid. This crudeproduct and the compound obtained in Referential Example 253 weredissolved in N,N-dimethylformamide (15 ml), and 1-hydroxybenzotriazolemonohydrate (164 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (251 mg) were added to stir the mixture at roomtemperature for 64.5 hours. The solvent was distilled off under reducedpressure, a saturated aqueous solution of sodium hydrogencarbonate andmethylene chloride were added to the residue to conduct liquidseparation, and the resultant organic layer was dried over anhydroussodium sulfate. After the solvent was distilled off under reducedpressure, the residue was purified by column chromatography on silicagel (methylene chloride:methanol=47:3). The thus-obtained pale yellowsolids were dissolved in methylene chloride, a 1N ethanol solution (0.52ml) of hydrochloric acid was added, and the solvent was distilled offunder reduced pressure. Methanol and diethyl ether were added to theresidue, and precipitate formed was collected by filtration to obtainthe title compound (245 mg).

¹H-NMR (DMSO-d₆) δ: 1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 1.95-2.10 (2H,m), 2.79 (3H, s), 2.80-3.00 (1H, m), 2.92 (3H, s), 2.94 (3H, s),3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.40-4.80 (3H,m), 7.40 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz), 8.75 (1H, d, J=7.1Hz), 9.00-9.10 (1H, br), 10.81 (1H, s), 11.45-11.75 (1H, m).

MS (FAB) m/z: 547 (M+H)⁺.

Example 192N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (240 mg) obtained in Referential Example 243 was dissolvedin tetrahydrofuran (8.0 ml), lithium hydroxide (41 mg) and water (1.0ml) were successively added to the solution, and the mixture was stirredat room temperature for 2.5 hours. The reaction mixture was concentratedunder reduced pressure to obtain lithium2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (249 mg).

On the other hand, 10% palladium on carbon (200 mg) was added to asolution of the compound (293 mg) obtained in Referential Example 252 inmethanol (10 ml), and the mixture was stirred at room temperature for 18hours under a hydrogen atmosphere. After removing palladium on carbon byfiltration, the filtrate was concentrated under reduced pressure toobtain a crude product (259 mg) ofN-{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide.

This crude product (259 mg) and the lithium salt (249 mg) prepared abovewere added to N,N-dimethylformamide (15 ml), and 1-hydroxybenzotriazolemonohydrate (166 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (235 mg) were added to stir the mixture at roomtemperature for 63.5 hours. The solvent was distilled off under reducedpressure, a saturated aqueous solution of sodium hydrogencarbonate andmethylene chloride were added to the residue to conduct liquidseparation, and the resultant organic layer was dried over anhydroussodium sulfate. After the solvent was distilled off under reducedpressure, the residue was purified by column chromatography on silicagel (methylene chloride:methanol=93:7). The thus-obtained pale yellowsolids were dissolved in methylene chloride, a 1N ethanol solution(0.855 ml) of hydrochloric acid was added to the solution, and thesolvent was distilled off under reduced pressure. Methanol and diethylether were added to the residue, and precipitate formed was collected byfiltration to obtain the title compound (209 mg).

¹H-NMR (DMSO-d₆) δ: 1.40-1.57 (1H, m), 1.60-1.80 (3H, m), 1.95-2.13 (2H,m), 2.79 (3H, s), 2.80-3.00 (1H, m), 2.92 (3H, s), 2.94 (3H, s),3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.37-4.80 (3H,m), 7.90-8.10 (2H, m), 8.45 (1H, d, J=2.2 Hz), 8.71 (1H, d, J=7.6 Hz),9.10-9.30 (1H, br), 10.26 (1H, s), 11.30-11.60 (1H, br).

MS (FAB) m/z: 548 (M+H)⁺.

Example 193N¹-(3-Chlorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (222 mg) obtained in Referential Example 270 and3-chloroaniline (63 μl) were dissolved in N,N-dimethylformamide (10 ml),and 1-hydroxybenzotriazole monohydrate (68 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144 mg)were added to stir the mixture at room temperature for 40 hours. Thesolvent was distilled off under reduced pressure, a saturated aqueoussolution of sodium hydrogencarbonate and methylene chloride were addedto the residue to conduct liquid separation, and the resultant organiclayer was dried over anhydrous sodium sulfate. After the solvent wasdistilled off under reduced pressure, the residue was purified by columnchromatography on silica gel (methylene chloride:methanol=30:1). Thethus-obtained pale yellow solids were dissolved in methylene chloride, a1N ethanol solution (0.50 ml) of hydrochloric acid was added, and thesolvent was distilled off under reduced pressure. Diethyl ether wasadded to the residue, and precipitate formed was collected by filtrationto obtain the title compound (174 mg).

¹H-NMR (DMSO-d₆) δ: 1.45-1.62 (1H, m), 1.65-1.90 (3H, m), 1.98-2.20 (2H,m), 2.79 (3H, s), 2.88-3.10 (1H, m), 2.93 (3H, s), 2.94 (3H, s),3.15-3.40 (2H, m), 3.40-3.90 (2H, m), 3.95-4.10 (1H, m), 4.40-4.80 (3H,m), 7.19 (1H, dd, J=9.3, 2.0 Hz), 7.37 (1H, d, J=8.2 Hz), 7.77 (1H, d,J=8.3 Hz), 7.92-8.05 (1H, m), 8.75 (1H, d, J=7.3 Hz), 8.95-9.20 (1H,br), 10.87 (1H, s), 11.25-11.45 (1H, br).

Example 194N¹-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N²-(4-fluorophenyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 254, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.40-2.13 (6H, m), 2.77 (3H, s), 2.93 (3H, s), 2.97(3H, s), 3.12-3.82 (7H, m), 3.93-4.04 (1H, m), 4.38-4.46 (1H, m),4.35-4.75 (1H, m), 7.11-7.21 (2H, m), 7.72-7.84 (2H, m), 8.73 (1H, d,J=7.6 Hz), 8.93-9.02 (1H, m), 10.70 (1H, s).

MS (FAB) m/z: 531 (M+H)⁺.

Example 195N¹-(4-Bromophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (152 mg) obtained in Referential Example 255 was dissolvedin tetrahydrofuran (5.0 ml), a 1N aqueous solution (1.20 ml) of sodiumhydroxide and methanol (5.0 ml) were successively added, and the mixturewas stirred at room temperature for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure, and methylene chloride (10 ml) and1N hydrochloric acid (2.0 ml) were added to the residue to conductliquid separation. The resultant organic layer was dried over anhydroussodium sulfate, and the solvent was distilled off under reduced pressureto obtain a crude product (280 mg) of 2-(4-bromoanilino)-2-oxoaceticacid as a colorless solid. This crude product and the compound (280 mg)obtained in Referential Example 253 were dissolved inN,N-dimethylformamide (30 ml), and 1-hydroxybenzotriazole monohydrate(90 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(226 mg) were added to stir the mixture at room temperature for a night.The solvent was distilled off under reduced pressure, a saturatedaqueous solution of sodium hydrogencarbonate and methylene chloride wereadded to the residue to conduct liquid separation, and the resultantorganic layer was dried over anhydrous sodium sulfate. After the solventwas distilled off under reduced pressure, the residue was purified bycolumn chromatography on silica gel (methylene chloride:methanol=97:3).The thus-obtained pale yellow solids were dissolved in methylenechloride, a 1N ethanol solution (191 μl) of hydrochloric acid was added,and the solvent was distilled off under reduced pressure. Methanol anddiethyl ether were added to the residue, and precipitate formed wascollected by filtration to obtain the title compound (103 mg).

¹H-NMR (DMSO-d₆) δ: 1.43-1.57 (1H, m), 1.59-1.80 (3H, m), 1.97-2.10 (2H,m), 2.79 (3H, s), 2.84-2.98 (7H, m), 3.18 (2H, br.s), 3.39-3.72 (2H, m),3.95-4.05 (1H, m), 4.20-4.80 (3H, m), 7.53 (2H, d, J=8.8 Hz), 7.77 (2H,d, J=8.8 Hz), 8.75 (1H, d, J=7.3 Hz), 8.97-9.09 (1H, m), 10.82 (1H, s),11.11 (1H, br.s).

MS (FAB) m/z: 591 (M+H)⁺.

Example 196N¹-(4-Chloro-2-methylphenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 256, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d6) δ: 1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 2.00-2.10 (2H,m), 2.19 (3H, s), 2.79 (3H, s), 2.80-3.00 (7H, m), 3.31 (2H, br.s),3.40-3.70 (2H, br), 3.95-4.05 (1H, m), 4.35-4.70 (3H, m), 7.20-7.30 (1H,m), 7.35 (1H, d, J=2.5 Hz), 7.43 (1H, d, J=8.6 Hz), 8.76 (1H, d, J=6.6Hz), 9.00-9.15 (1H, br), 10.19 (1H, s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 197N¹-(4-Chloro-3-methylphenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 257, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.47-1.53 (1H, m), 1.68-1.80 (3H, m), 1.98-2.09 (2H,m), 2.29 (3H, s), 2.79 (3H, s), 2.80-3.00 (1H, m), 2.95 (6H, s),3.17-3.19 (3H, m), 3.40-3.80 (1H, m), 3.93-4.02 (1H, m), 4.44-4.56 (3H,m), 7.38 (1H, d, J=8.8 Hz), 7.65 (1H, d, J=8.8 Hz), 7.74 (1H, s), 8.75(1H, d, J=7.8 Hz), 8.96 (1H, d, J=8.0 Hz), 10.69 (1H, s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 198N¹-(4-Chloro-2-fluorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 258, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.40-1.55 (1H, m), 1.58-1.80 (3H, m), 1.95-2.12 (2H,m), 2.77 (3H, s), 2.80-3.00 (1H, m), 2.91 (3H, s), 2.92 (3H, s),3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.30-4.80 (3H,m), 7.29 (1H, d, J=8.5 Hz), 7.52 (1H, dd, J=10.3, 2.0 Hz), 7.61 (1H, t,J=8.4 Hz), 8.72 (1H, d, J=6.8 Hz), 9.00-9.20 (1H, br), 10.38 (1H, s),11.20-11.45 (1H, br).

MS (FAB) m/z: 565 (M+H)⁺.

Example 199N¹-(2,4-Dichlorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (300 mg) obtained in Referential Example 270 was dissolvedin N,N-dimethylformamide (5 ml), and 2,4-dichloroaniline (165 mg),1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260 mg) and1-hydroxybenzotriazole monohydrate (91 mg) were added to stir themixture at room temperature for 2 days. The solvent was distilled offunder reduced pressure, a saturated aqueous solution of sodiumhydrogencarbonate and methylene chloride were added to the residue toconduct liquid separation, and the resultant organic layer was driedover anhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by column chromatography onsilica gel (methylene chloride:methanol=47:3) to obtain a free base ofthe title compound. This product was dissolved in methylene chloride, a1N ethanol solution (108 μl) of hydrochloric acid was added, and thesolvent was distilled off under reduced pressure. A small amount ofmethanol was added to the residue, and diethyl ether was added dropwisewhile irradiating with ultrasonic waves to collect precipitate formed byfiltration. This product was washed with diethyl ether to obtain thetitle compound (60 mg).

¹H-NMR (DMSO-d₆) δ: 1.45-1.77 (4H, m), 2.03-2.12 (2H, m), 2.79 (3H, s),2.92-2.96 (7H, m), 3.25 (2H, br.s), 3.49 (1H, br.s), 3.69 (1H, br.s),3.98-4.04 (1H, m), 4.40-4.43 (1H, m), 4.45 (1H, br.s), 4.69 (1H, br.s),7.48 (1H, dd, J=8.5, 2.4 Hz), 7.75 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=8.5Hz), 8.75 (1H, d, J=6.8 Hz), 9.21 (1H, br.s), 10.25 (1H, s), 11.55 (1H,br.s).

MS (FAB) m/z: 581 (M+H)⁺.

Example 200N¹-(3,4-Dichlorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide

3,4-Dichloroaniline (1.62 g) was dissolved in methylene chloride (20ml), and triethylamine (1.67 ml) and methyl chlorooxoacetate (1.01 ml)were successively added under ice cooling, and the mixture was stirredat room temperature for 21 hours. Water and methylene chloride wereadded to the reaction mixture to conduct liquid separation. Theresultant water layer was extracted with methylene chloride. Organiclayers were combined and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas dissolved in ethanol (50 ml), and water (25 ml) and lithiumhydroxide monohydrate (629 mg) were successively added to stir themixture at room temperature for 12.5 hours. Lithium hydroxidemonohydrate (629 mg) was additionally added to stir the mixture at roomtemperature for 5.5 hours. The reaction mixture was concentrated underreduced pressure to solidity. Water and diethyl ether were added to theresidue to conduct liquid separation. Hydrochloric acid was added to theresultant water layer to acidify it. Solid formed were collected byfiltration to obtain a crude product (1.62 g) of2-(3,4-dichloroanilino)-2-oxoacetic acid as a colorless solid. Thiscrude product (191 mg) and the compound obtained in Referential Example253 were dissolved in N,N-dimethylformamide (10 ml), and1-hydroxybenzotriazole monohydrate (110 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg)were added to stir the mixture at room temperature for 67 hours. Thesolvent was distilled off under reduced pressure, a saturated aqueoussolution of sodium hydrogencarbonate and ethyl acetate were added to theresidue to conduct liquid separation, and the resultant water layer wasextracted 3 times with methylene chloride. Organic layers were combinedand dried over anhydrous sodium sulfate. After the solvent was distilledoff under reduced pressure, the residue was purified by columnchromatography on silica gel (methylene chloride:methanol=95:5) toobtain the title compound (154 mg).

¹H-NMR (CDCl₃) δ: 1.77-1.88 (1H, m), 1.91-1.95 (1H, m), 2.05-2.10 (3H,m), 2.51 (3H, s), 2.77-2.99 (6H, m), 2.95 (3H, s), 3.05 (3H, s), 3.68(1H, d, J=15.5 Hz), 3.74 (1H, d, J=15.5 Hz), 4.08-4.13 (1H, m),4.69-4.72 (1H, m), 7.40 (2H, s), 7.41 (1H, d, J=7.7 Hz), 7.90 (1H, s),8.01 (1H, d, J=7.7 Hz), 9.27 (1H, s).

MS (ESI) m/z: 581 (M+H)⁺.

Example 201N¹-(2,4-Difluorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 259 and condensing the hydrolyzate with the compoundobtained in Referential Example 253 in a similar manner to the processdescribed in Example 191.

¹H-NMR (CDCl₃) δ: 1.55-1.62 (1H, m), 1.67-1.98 (2H, m), 2.01-2.18 (4H,m), 2.52 (3H, s), 2.77-3.00 (4H, m), 2.95 (3H, s), 2.99 (3H, s),3.65-3.78 (2H, m), 4.06-4.15 (1H, m), 4.66-4.73 (1H, m), 6.85-6.94 (2H,m), 7.38 (1H, d, J=8.5 Hz), 7.96 (1H, d, J=7.3 Hz), 8.22-8.29 (1H, m),9.36 (1H, br).

Example 202N¹-(3,4-Difluorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 260 and condensing the hydrolyzate with the compoundobtained in Referential Example 253 in a similar manner to the processdescribed in Example 191.

¹H-NMR (CDCl₃) δ: 1.56-1.73 (1H, m), 1.77-1.99 (2H, m), 2.00-2.18 (4H,m), 2.52 (3H, s), 2.75-3.00 (4H, m), 2.95 (3H, s), 3.06 (3H, s),3.64-3.79 (2H, m), 4.05-4.14 (1H, m), 4.68-4.75 (1H, m), 7.09-7.21 (2H,m), 7.38 (1H, d, J=8.8 Hz), 7.72 (1H, ddd, J=12.0, 7.1, 2.6 Hz), 7.95(1H, d, J=7.8 Hz), 9.22 (1H, br).

Example 203N¹-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N²-(pyridin-4-yl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 261, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.40-2.10 (6H, m), 2.77 (3H, s), 2.927 (3H, s),2.933 (3H, s), 3.05-4.20 (8H, m), 4.40-4.55 (1H, m), 8.27 (2H, d, J=6.8Hz), 8.67 (1H, d, J=8.0 Hz), 8.71 (2H, d, J=6.8 Hz), 9.10-9.30 (1H, br),11.81 (1H, s).

MS (FAB) m/z: 514 (M+H)⁺.

Example 204N¹-(5-Bromopyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 262, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 195.

¹H-NMR (DMSO-d₆) δ: 1.43-1.57 (1H, m), 1.61-1.81 (3H, m), 1.98-2.15 (2H,m), 2.79 (3H, s), 2.86 (3H, s), 2.89-3.01 (4H, m), 3.18 (2H, br.s), 3.50(2H, br.s), 3.95-4.05 (1H, m), 4.35-4.62 (3H, m), 7.97 (1H, d, J=9.0Hz), 8.12 (1H, dd, J=9.0, 2.4 Hz), 8.52 (1H, d, J=2.4 Hz), 8.70 (1H, d,J=7.5 Hz), 9.18 (1H, d, J=7.5 Hz), 10.25 (1H, br.s).

MS (FAB) m/z: 592 (M+H)⁺.

Example 205N¹-(6-Chloropyridin-3-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (200 mg) obtained in Referential Example 263, which was acrude product, was dissolved in methanol (10 ml) to heat the solution to50° C., and a 1N aqueous solution (3 ml) of sodium hydroxide to stir themixture for 5 minutes. To this mixture was added 1N hydrochloric acid toadjust the pH to a weak acidity. The solvent was distilled off underreduced pressure to obtain residue containing2-[(2-chloropyridin-5-yl)amino]-2-oxoacetic acid. This residue and thecompound (250 mg) obtained in Referential Example 253 were dissolved inN,N-dimethylformamide (5 ml), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg) and1-hydroxybenzotriazole monohydrate (46 mg) were added to stir themixture at room temperature for 3 days. The solvent was distilled offunder reduced pressure, and a saturated aqueous solution of sodiumhydrogencarbonate and methylene chloride were added to the residue toconduct liquid separation. The resultant organic layer was dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methylene chloride:methanol=47:3) to obtain a free base ofthe title compound as a pale yellow solid. This product was dissolved inmethylene chloride, a 1N ethanol solution (862 μl) of hydrochloric acidwas added, and the solvent was distilled off under reduced pressure. Asmall amount of methanol was added to the residue, and ethyl acetate anddiethyl ether were added dropwise while irradiating with ultrasonicwaves to collect precipitate formed by filtration. This product waswashed with diethyl ether to obtain the title compound (229 mg).

¹H-NMR (DMSO-d₆) δ: 1.46-1.75 (4H, m), 1.99-2.09 (2H, m), 2.79 (3H, s),2.92-2.95 (7H, m), 3.12-3.53 (3H, m), 3.70 (1H, br.s), 3.99-4.06 (1H,m), 4.44 (2H, br.s), 4.69, 4.73 (1H, each s), 7.53 (1H, d, J=8.5 Hz),8.23-8.25 (1H, m), 8.72-8.77 (1H, m), 8.85 (1H, s), 9.07, 9.16 (1H, eachd, J=8.1 Hz), 11.09 (1H, d, J=8.1 Hz), 11.78 (1H, br.s).

MS (FAB) m/z: 548 (M+H)⁺.

Example 206N¹-(6-Chloropyridazin-3-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 264, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.44-1.57 (1H, m), 1.62-1.80 (3H, m), 2.00-2.10 (2H,m), 2.79 (3H, s), 2.86 (3H, br.s), 2.94 (3H, s), 2.95-3.01 (1H, m),3.14-3.23 (2H, m), 3.45-3.63 (2H, m), 3.96-4.08 (1H, m), 4.40-4.60 (3H,m), 7.97 (1H, d, J=9.3 Hz), 8.26 (1H, d, J=9.3 Hz), 8.69 (1H, d, J=7.6Hz), 9.20 (1H, d, J=7.6 Hz), 11.06 (1H, s).

MS (FAB) m/z: 549 (M+H)⁺.

Example 207N¹-(5-Chlorothiazol-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 265, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.35-2.10 (6H, m), 2.77 (3H, s), 2.92 (3H, s), 2.93(3H, s), 3.05-4.23 (8H, m), 4.32-4.80 (2H, m), 7.59 (1H, s), 8.63 (1H,d, J=7.6 Hz), 9.14 (1H, d, J=7.6 Hz).

MS (FAB) m/z: 554 (M+H)⁺.

Example 208N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (210 mg) obtained in Referential Example 266 and thecompound (350 mg) obtained in Referential Example 272 were dissolved inN,N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate(205 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(290 mg) were added to stir the mixture at room temperature for 20hours. The solvent was distilled off under reduced pressure, and asaturated aqueous solution of sodium hydrogencarbonate and methylenechloride were added to the residue to conduct liquid separation. Theresultant organic layer was dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (methylenechloride:methanol=20:1). The thus-obtained pale yellow solids weredissolved in methylene chloride, a 1N ethanol solution (0.46 ml) ofhydrochloric acid was added, and the solvent was distilled off underreduced pressure. Methanol and diethyl ether were added to the residue,and precipitate formed was collected by filtration to obtain the titlecompound (248 mg).

¹H-NMR (DMSO-d₆) δ: 1.47-1.50 (1H, m), 1.69-1.76 (3H, m), 1.98-2.06 (2H,m), 2.79 (3H, s), 2.95 (3H, s), 2.98-3.05 (1H, m), 3.10 (3H, s),3.49-4.62 (6H, m), 7.98-8.03 (2H, m), 8.45 (1H, s), 8.73 (1H, d, J=7.6Hz), 9.10 (1H, d, J=8.0 Hz), 10.30 (1H, s).

MS (FAB) m/z: 534 (M+H)⁺.

Example 209N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)acetyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (2.3 g) obtained in Referential Example 267 was dissolvedin ethanol (10 ml), and a 1N aqueous solution (20 ml) of sodiumhydroxide was added to stir the mixture at room temperature for 2 hours.After 1N hydrochloric acid (20 ml) was added to the reaction mixture,the mixture was diluted with water and stirred for 30 minutes. Insolublematter deposited was collected by filtration to obtain2-(4-chloroanilino)acetic acid (1.05 g) as a colorless solid. This solidand the compound (0.25 g) obtained in Referential Example 253 weredissolved in N,N-dimethylformamide (10 ml), and 1-hydroxybenzotriazolemonohydrate (0.11 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.23 g) were added to stir the mixture at roomtemperature for 4 days. After the reaction mixture was diluted withchloroform and washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated aqueous solution of sodium chloride, theresultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel(chloroform:methanol=97:3). The thus-obtained pale yellow solid wasdissolved in ethanol, a 1N ethanol solution of hydrochloric acid wasadded, and the solvent was distilled off under reduced pressure.Methanol and diethyl ether were added to the residue, and precipitateformed was collected by filtration to obtain the title compound (0.15g).

¹H-NMR (DMSO-d₆) δ: 1.35-1.41 (1H, m), 1.59-1.80 (3H, m), 1.82-1.95 (2H,m), 2.76 (3H, s), 2.93 (3H, s), 2.94 (3H, s), 2.99-3.10 (1H, m),3.10-3.22 (2H, m), 3.42-3.60 (2H, m), 3.60-3.77 (2H, m), 3.80-3.90 (1H,m), 4.35-4.48 (2H, m), 4.68-4.80 (1H, m), 6.40 (1H, d, J=6.7 Hz), 6.44(1H, d, J=6.7 Hz), 6.90 (1H, d, J=6.7 Hz), 7.00 (1H, d, J=6.7 Hz),7.70-7.89 (1H, m), 8.35-8.42 (1H, m), 11.05-11.38 (1H, m).

Example 210N-{(1R,2S,5S)-2-{[2-(4-Chloro-2-fluoroanilino)acetyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 268, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 209.

¹H-NMR (DMSO-d₆) δ: 1.35-1.42 (1H, m), 1.55-1.78 (3H, m), 1.80-2.00 (2H,m), 2.76 (3H, s), 2.92 (3H, s), 2.94 (3H, s), 2.99-3.10 (1H, m),3.10-3.22 (2H, m), 3.42-3.60 (2H, m), 3.60-3.77 (2H, m), 3.85-4.00 (1H,m), 4.33-4.48 (2H, m), 4.65-4.80 (1H, m), 6.41 (1H, t, J=8.8 Hz), 6.73(1H, dt, J=8.8, 1.2 Hz), 7.08 (1H, dd, J=11.7, 1.2 Hz), 7.78-7.92 (1H,m), 8.35-8.42 (1H, m), 11.18-11.50 (1H, m).

Example 211N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 432 with the compound obtained in ReferentialExample 34 and then treating the condensation product with hydrochloricacid in a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.70-2.15 (6H, m), 2.80 (3H, s),2.97 (3H, s), 2.95-3.15 (2H, m), 3.35-3.55 (2H, m), 4.05-4.20 (1H, m),4.46 (2H, s), 4.50-4.65 (1H, m), 7.05 (1H, s), 7.16 (1H, dd, J=8.8, 2.2Hz), 7.41 (1H, d, J=8.8 Hz), 7.68 (1H, s), 8.30-8.45 (1H, br), 9.30-9.50(1H, br), 11.78 (1H, s).

MS (ESI) m/z: 529 (M+H)⁺.

Example 212N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-(4,5-dihydrooxazol-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (250 mg) obtained in Example 211 was suspended in methylenechloride, and a saturated aqueous solution of sodium hydrogencarbonatewas added to fully stir the mixture. The resultant organic layer wasseparated and dried over anhydrous magnesium sulfate. Triethylamine (0.5ml) and bromoethyl isocyanate (43 μl) were then added to stir themixture at room temperature for 20 hours. A saturated aqueous solutionof sodium hydrogencarbonate was added to the reaction mixture toseparate an organic layer. The organic layer was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methylene chloride:methanol=22:3) to obtain the title compound (227mg).

¹H-NMR (CDCl₃) δ: 1.50-2.15 (4H, m), 2.15-2.40 (2H, m), 2.80-3.00 (1H,m), 2.97 (3H, s), 3.11 (3H, s), 3.70-3.95 (4H, m), 4.10-4.30 (1H, m),4.30-4.50 (2H, m), 4.60-4.70 (1H, m), 4.74 (2H, s), 6.85 (1H, s), 7.21(1H, dd, J=8.8, 2.2 Hz), 7.34 (1H, d, J=8.8 Hz), 7.50 (1H, br.s), 7.62(1H, s), 7.87 (1H, br.s), 9.48 (1H, br.s).

MS (ESI) m/z: 598 (M+H)⁺.

Example 213N-{(1R,2S,5S)-2-{[(5-Chloro-4-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (140 mg) obtained in Referential Example 144 was dissolvedin N,N-dimethylformamide (10 ml), and the compound (100 mg) obtained inReferential Example 274, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (140 mg) and 1-hydroxybenzotriazole monohydrate (110 mg)were added to stir the mixture at room temperature for 18 hours. Thesolvent was distilled off under reduced pressure, and the residue waspartitioned in water-ethyl acetate, and a water layer was extracted withethyl acetate. The resultant organic layers were combined, washed withsaturated aqueous solution of sodium chloride and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:methylene chloride=1:19), giving tert-butyl(1R,2S,5S)-2-{[(5-chloro-4-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate(260 mg).

The thus-obtained powder was dissolved in methylene chloride (5 ml), anda 4N dioxane solution (1.2 ml) of hydrochloric acid was added. After thereaction mixture was stirred at room temperature for 3.5 hours, thesolvent was distilled off under reduced pressure. Methylene chloride (10ml) was added to the residue, and the mixture was concentrated. Afterthis process was repeated 3 times, the residue was dried under reducedpressure to obtain crudeN-{(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-5-chloro-4-fluoroindole-2-carboxamide.This product was dissolved in N,N-dimethylformamide (50 ml), and thecompound (150 mg) obtained in Referential Example 10,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg) and1-hydroxybenzotriazole monohydrate (110 mg) were added to stir themixture at room temperature for 18 hours. The solvent was distilled offunder reduced pressure, and the residue was partitioned in a mixedsolvent of water-ethyl acetate-tetrahydrofuran, and a water layer wasextracted with ethyl acetate. The resultant organic layers werecombined, washed with saturated aqueous solution of sodium chloride andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (methanol:methylene chloride=1:19) toobtain a free base of the title compound (270 mg). This product wasdissolved in methylene chloride (10 ml), and a 1N ethanol solution (0.72ml) of hydrochloric acid was added to stir the mixture at roomtemperature for 30 minutes. Crystals deposited were collected byfiltration to obtain the title compound (200 mg).

¹H-NMR (DMSO-d₆) δ: 1.24-1.98 (6H, m), 2.33-3.33 (6H, m), 2.81 (3H, s),2.90 (3H, s), 2.99 (3H, s), 4.12 (1H, br.s), 4.30-4.70 (1H, m), 4.60(1H, br.s), 7.21 (1H, s), 7.27 (2H, br.s), 8.37 (1H, d, J=8.1 Hz), 8.43(1H, d, J=7.6 Hz), 12.11 (1H, s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 214N-{(1R,2S,5S)-2-{[(5-Chloro-3-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (250 mg) obtained in Referential Example 279 was dissolvedin methylene chloride (60 ml), and a 4N dioxane solution (1.3 ml) ofhydrochloric acid was added. After the reaction mixture was stirred atroom temperature for 5.5 hours, a 4N dioxane solution (0.65 ml) ofhydrochloric acid was additionally added, and the mixture was stirred atroom temperature for 1 hour. The solvent was distilled off under reducedpressure, methylene chloride (10 ml) was added to the residue, and themixture was concentrated. This process was repeated 3 times. The residuewas dried under reduced pressure, and the thus-obtained crude productwas dissolved in N,N-dimethylformamide (50 ml), and the compound (160mg) obtained in Referential Example 10,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg) and1-hydroxybenzotriazole monohydrate (120 mg) were added to stir themixture at room temperature for 18 hours. The solvent was distilled offunder reduced pressure, and the residue was partitioned in a mixedsolvent of water-ethyl acetate, and a water layer was extracted withethyl acetate. The resultant organic layers were combined, washed withsaturated aqueous solution of sodium chloride and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified twice by column chromatography onsilica gel (methanol:methylene chloride=2:23→1:9) to obtain a free base(260 mg) of the title compound. This product was dissolved in methylenechloride, and a 1N ethanol solution (0.69 ml) of hydrochloric acid wasadded to stir the mixture at room temperature for 30 minutes. Thesolvent was distilled off. The residue was dissolved in methanol, anddiethyl ether and hexane were added. The thus-obtained crystals werecollected by filtration to obtain the title compound (230 mg).

¹H-NMR (DMSO-d₆) δ: 1.50-1.56 (1H, m), 1.73-1.78 (3H, m), 1.94-2.02 (2H,m), 2.33-3.55 (6H, m), 2.80 (3H, s), 2.92 (3H, s), 2.98 (3H, s), 4.17(1H, br.s), 4.30-4.80 (1H, br), 4.62 (1H, br.s), 7.25 (1H, d, J=8.8, 1.7Hz), 7.40 (1H, d, J=8.8, 1.7 Hz), 7.65 (1H, d, J=1.7 Hz), 7.72 (1H, d,J=5.9 Hz), 8.74 (1H, d, J=8.0 Hz), 11.12 (1H, br), 11.71 (1H, s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 215N-{(1R,2S,5S)-2-{[(3-Bromo-5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 282 with a 4N dioxane solution of hydrochloric acidand condensing the-thus treated compound with the compound obtained inReferential Example 10 in a similar manner to the process described inExample 214.

¹H-NMR (DMSO-d₆) δ: 1.51-2.01 (6H, m), 2.33-3.29 (7H, m), 2.81 (3H, s),2.88 (3H, s), 3.01 (3H, s), 4.20 (1H, br.s), 4.48 (1H, br), 4.70-4.73(1H, m), 7.29 (1H, dd, J=8.9, 1.8 Hz), 7.45-7.49 (2H, m), 7.80 (1H, d,J=7.6 Hz), 8.76 (1H, d, J=8.8 Hz), 12.31 (1H, s).

MS (FAB) m/z: 622 (M+H)⁺.

Example 216N-{(1R,2S,5S)-2-{[(3-Chloro-5-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 253 and the compound obtained in Referential Example284 in a similar manner to the process described in Example 5.

¹H-NMR (DMSO-d6) δ: 1.40-1.51 (1H, m), 1.75-2.00 (5H, m), 2.79 (3H, s),2.92 (3H, s), 2.99 (3H, s), 3.10-3.21 (3H, m), 3.29-3.41 (4H, m),4.11-4.21 (1H, m), 4.62-4.75 (1H, m), 7.14 (1H, dt, J=8.8, 2.4 Hz), 7.24(1H, dd, J=8.8, 2.4 Hz), 7.45 (1H, dd, J=8.8, 4.4 Hz), 7.69 (1H, d,J=2.5 Hz), 8.79 (1H, d, J=2.5 Hz), 12.10 (1H, s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 217N-{(1R,2S,5S)-2-{[(5-Chloro-3-formylindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 253 and the compound obtained in Referential Example286 in a similar manner to the process described in Example 5.

¹H-NMR (DMSO-d6) δ: 1.40-1.51 (1H, m), 1.75-1.89 (4H, m), 1.90-2.01 (1H,m), 2.80 (3H, s), 2.91 (3H, s), 3.03 (3H, s), 3.05-3.33 (3H, m),3.60-3.71 (1H, m), 4.11-4.21 (1H, m), 4.32-4.44 (1H, m), 4.62-4.75 (2H,m), 7.35 (1H, dd, J=8.0, 1.4 Hz), 7.56 (1H, d, J=8.0 Hz), 8.21 (1H, d,J=1.4 Hz), 8.65 (1H, t, J=7.4 Hz), 9.92 (1H, d, J=6.8 Hz), 10.15 (1H, t,J=9.1 Hz), 13.00 (1H, dt, J=6.4).

MS (FAB) m/z: 571 (M+H)⁺.

Example 2185-Chloro-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl-N³,N³-dimethylindole-2,3-dicarboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 253 and the compound obtained in Referential Example289 in a similar manner to the process described in Example 5.

¹H-NMR (DMSO-d6) δ: 1.40-1.51 (1H, m), 1.75-2.01 (5H, m), 2.78 (9H, s),2.93 (3H, s), 3.01 (3H, s), 3.10-3.33 (3H, m), 3.40-3.50 (1H, m),3.65-3.75 (1H, m), 4.01-4.09 (1H, m), 4.32-4.44 (1H, m), 4.62-4.75 (2H,m), 7.25 (1H, d, J=8.0 Hz), 7.40-7.50 (2H, m), 8.62 (1H, br), 9.08 (1H,br), 12.28 (1H, br).

MS (FAB) m/z: 614 (M+H)⁺.

Example 219N-{(1R,2S,5S)-2-[(6-Chloro-2-naphthoyl)amino]-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (270 mg) obtained in Referential Example 294 was dissolvedin methylene chloride (10 ml), and a 1N ethanol solution (10 ml) ofhydrochloric acid was added to stir the mixture for 90 minutes. Thesolvent was distilled off under reduced pressure, and the resultantresidue was dissolved in N,N-dimethylformamide (7 ml). The compound (110mg) obtained in Referential Example 10,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg) and1-hydroxybenzotriazole monohydrate (70 mg) were added to stir themixture at room temperature for 23 hours. The reaction mixture wasconcentrated under reduced pressure, and water was added to conductextraction with ethyl acetate. The resultant organic layer was driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified twice by columnchromatography on silica gel (methylene chloride:methanol=20:1→10:1).The thus-obtained free base was dissolved in methanol, and a 1N ethanolsolution (0.30 ml) of hydrochloric acid was added. The residue waswashed with ethyl acetate to obtain the title compound (130 mg).

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.10 (2H,m), 2.81 (3H, s), 2.91 (3H, s), 3.00 (3H, s), 3.00-3.22 (3H, m), 3.53(2H, br), 4.10-4.20 (1H, m), 4.30-4.70 (3H, m), 7.59 (1H, dd, J=8.8, 2.2Hz), 7.87 (1H, d, J=8.5 Hz), 7.96 (1H, d, J=8.5 Hz), 8.02 (1H, d, J=8.8Hz), 8.10 (1H, d, J=2.2 Hz), 8.33 (1H, s), 8.43 (1H, d, J=8.1 Hz), 8.52(1H, d, J=7.3 Hz).

MS (FAB) m/z: 554 (M+H)⁺.

Example 2207-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 299 with an ethanol solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example10 in a similar manner to the process described in Example 219.

¹H-NMR (CDCl₃) δ: 1.50-1.65 (1H, m), 1.70-1.90 (3H, m), 2.05-2.15 (1H,m), 2.15-2.30 (1H, m), 2.81 (3H, s), 2.85-3.05 (8H, m), 3.15-3.25 (2H,m), 3.40-3.80 (1H, m), 4.25-4.80 (4H, m), 8.02 (1H, dd, J=8.8, 2.0 Hz),8.38 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.91 (1H, s), 8.96 (1H, d, J=7.3Hz), 9.53 (1H, br).

MS (FAB) m/z: 556 (M+H)⁺.

Example 221N-{(1R,2S,5S)-2-{[(5-Chlorobenzimidazol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 300 with an ethanol solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example10 in a similar manner to the process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.60-1.83 (3H, m), 2.00-2.20 (2H,m), 2.78 (3H, s), 2.92 (6H, s), 3.00-3.30 (3H, m), 3.47 (2H, br.s),4.10-4.75 (4H, m), 7.30 (1H, d, J=8.8 Hz), 7.62 (1H, d, J=12.5 Hz), 7.63(1H, s), 8.75-8.87 (1H, m), 9.09 (1H, dd, J=12.5, 8.8 Hz), 11.2-11.4(1H, m).

MS (FAB) m/z: 546 (M+H)⁺.

Example 222N-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-7-fluoroisoquinoline-3-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 253 and the compound obtained in Referential Example304 in a similar manner to the process described in Example 5.

¹H-NMR (DMSO-d₆) δ: 1.50-1.60 (1H, m), 1.70-1.85 (3H, m), 1.95-2.05 (1H,m), 2.10-2.20 (1H, m), 2.80 (3H, s), 2.90-3.90 (5H, m), 2.93 (3H, s),2.96 (3H, s), 4.10-4.75 (4H, m), 7.75-7.85 (1H, m), 8.00-8.05 (1H, m),8.30-8.35 (1H, m), 8.61 (1H, s), 8.93 (2H, d, J=7.3 Hz), 9.31 (1H, s).

MS (FAB) m/z: 539 (M+H)⁺.

Example 223N-{(1R,2S,5S)-2-{[(7-Chloro-2H-chromen-3-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The compound (220 mg) obtained in Referential Example 252 was dissolvedin methanol (10 ml), and 10% palladium on carbon (180 mg) was added tostir the mixture at room temperature for 4 hours in a hydrogenatmosphere. After the reaction mixture was filtered, the filtrate wasconcentrated under reduced pressure, and the residue was dissolved inN,N-dimethylformamide (30 ml). The compound (108 mg) obtained inReferential Example 306, 1-hydroxybenzotriazole monohydrate (78 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg)were added to stir the mixture at room temperature for a night. Thereaction mixture was concentrated under reduced pressure, and methylenechloride and a saturated aqueous solution of sodium hydrogencarbonatewere added to the residue to conduct liquid separation. The resultantorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methylene chloride:methanol=100:3)to obtain a pale yellow foamy substance. This foamy substance wasdissolved in methylene chloride (2 ml), a 1N ethanol solution (363 μl)of hydrochloric acid was added, and the solvent was distilled off underreduced pressure. Diethyl ether was added to the residue. Precipitateformed was collected by filtration to obtain the title compound (175mg).

¹H-NMR (DMSO-d₆) δ: 1.40-1.52 (1H, m), 1.55-1.96 (5H, m), 2.78 (3H, s),2.90 (3H, s), 2.98 (3H, s), 3.01-3.12 (1H, m), 3.13-3.28 (2H, m),3.40-3.85 (2H, m), 3.92-4.00 (1H, m), 4.35-4.80 (3H, m), 4.84 (1H, d,J=14.5 Hz), 4.89 (1H, d, J=14.5 Hz), 6.92 (1H, s), 6.98 (1H, dd, J=8.1,1.7 Hz), 7.08 (1H, s), 7.17 (1H, d, J=8.3 Hz), 8.12 (1H, d, J=8.1 Hz),8.34 (1H, d, J=8.1 Hz).

MS (FAB) m/z: 558 (M+H)⁺.

Example 224N-{(1R,2S,5S)-2-{[(E)-3-(4-Chlorophenyl)-2-propenoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 307 with an ethanol solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example10 in a similar manner to the process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.35-1.55 (1H, m), 1.55-1.90 (4H, m), 2.79 (3H, s),2.92 (3H, s), 2.99 (3H, s), 3.05-3.30 (3H, m), 3.40-3.55 (1H, m),3.60-3.75 (1H, m), 3.93-4.03 (2H, m), 4.35-4.50 (1H, m), 4.50-4.60 (1H,m), 4.60-4.75 (1H, m), 6.65 (1H, d, J=15.7 Hz), 7.35 (1H, d, J=15.7 Hz),7.44 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.6 Hz), 8.03 (1H, d, J=8.1 Hz),8.34 (1H, br.s), 11.25-11.70 (1H, br).

MS (ESI) m/z: 530 (M+H)⁺.

Example 2256-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-oxo-1,4-dihydroquinoline-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 253 and the compound obtained in Referential Example309 in a similar manner to the process described in Example 5.

¹H-NMR (DMSO-d₆) δ: 1.43-1.60 (1H, m), 1.65-2.10 (3H, m), 2.79 (3H, s),2.92 (3H, s), 2.99 (3H, s), 3.05-3.20 (2H, m), 3.20-3.80 (5H, m),4.08-4.20 (1H, m), 4.35-4.50 (1H, m), 4.60-4.70 (1H, m), 4.70 (1H, d,J=15.6 Hz), 6.77 (1H, br.s), 7.73 (1H, d, J=8.9 Hz), 7.94 (1H, d, J=8.9Hz), 7.97 (1H, d, J=2.2 Hz), 8.54 (1H, br.s), 8.80-9.00 (1H, m), 11.20(1H, br.d), 12.06 (1H, br.s).

MS (ESI) m/z: 571 (M+H)⁺.

Example 226 tert-Butyl2-[({(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate

1) The compound (1.46 g) obtained in Referential Example 310 wasdissolved in methylene chloride (10 ml), and an ethanol solution (10 ml)of hydrochloric acid was added at room temperature to stir the mixturefor 1 hour. After completion of the reaction, the solvent was distilledoff, ethanol was added, the mixture was concentrated, and diisopropylether was added to the residue to solidify it. The resultant solids werecollected by filtration to obtainN-{(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-5-chloroindole-2-carboxamidehydrochloride.

2) This product was dissolved in N,N-dimethylformamide (5 ml), and thecompound (1.31 g) obtained in Referential Example 406,1-hydroxybenzotriazole monohydrate (640 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.36 g)were added to stir the mixture at room temperature for 3 days. Thereaction mixture was concentrated, and methylene chloride and asaturated aqueous solution of sodium hydrogencarbonate were added to theresidue to conduct liquid separation. The resultant organic layer wasdried over anhydrous sodium sulfate. After the solvent was distilled offunder reduced pressure, the residue was purified by columnchromatography on silica gel (methanol:methylene chloride=1:19) toobtain the title compound (1.22 g).

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 1.70-2.40 (6H, m), 2.80-3.20 (7H, m),4.15-4.25 (1H, m), 4.55-4.80 (5H, m), 6.83 (1H, d, J=1.5 Hz), 7.20 (1H,dd, J=8.8, 2.0 Hz), 7.33 (1H, d, J=8.8 Hz), 7.40-7.50 (1H, m), 7.61 (1H,br.s), 7.72-7.80 (1H, m), 9.41 (1H, br.s).

MS (ESI) m/z: 615 (M+H)⁺.

Example 2275-Chloro-N-{(1S,2R,4S)-2-[[(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}-4-[(dimethylamino)carbonyl]cyclohexyl}indole-2-carboxamidehydrochloride

The compound (1.22 g) obtained in Referential Example 226 was dissolvedin methylene chloride (5 ml), and an ethanol solution (10 ml) ofhydrochloric acid was added to stir the mixture for 1 hour. After thereaction mixture was concentrated, a saturated aqueous solution ofsodium hydrogencarbonate and methylene chloride were added to conductliquid separation, and the resultant organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas purified by column chromatography on silica gel (methanol:methylenechloride=1:9) to obtain a free base (636 mg) of the title compound as acolorless glassy solid. The free base (200 mg) was dissolved in a 1Nethanol solution (1 ml) of hydrochloric acid. After the solution wasconcentrated, ethyl acetate was added to solidfy the residue. Thethus-obtained colorless powder was collected by filtration and dried toobtain the title compound (195 mg).

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.05 (2H,m), 2.80 (3H, s), 2.98 (3H, s), 2.98-3.15 (1H, m), 4.05-4.20 (1H, m),4.44 (2H, br.s), 4.58 (3H, br.s), 7.05 (1H, d, J=1.5 Hz), 7.16 (1H, dd,J=8.7, 1.8 Hz), 7.42 (1H, d, J=8.7 Hz), 7.68 (1H, d, J=1.8 Hz), 8.38(1H, d, J=7.8 Hz), 8.42 (1H, d, J=7.8 Hz), 10.45-10.65 (2H, br), 11.78(1H, br.s).

MS (FAB) m/z: 515 (M+H)⁺.

Example 2285-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)indole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example227 and formalin in a similar manner to the process described in Example18.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.65-1.90 (3H, m), 1.90-2.05 (2H,m), 2.80 (3H, s), 2.98 (3H, s), 2.98-3.06 (1H, m), 3.06 (3H, s),4.05-4.20 (1H, m), 4.30-5.00 (5H, br.s), 7.04 (1H, d, J=1.7 Hz), 7.17(1H, dd, J=8.8, 2.1 Hz), 7.41 (1H, d, J=8.8 Hz) 7.68 (1H, d, J=2.1 Hz)8.36 (1H, d, J=7.8 Hz), 8.42 (1H, d, J=8.1 Hz), 11.78 (1H, br.s), 12.14(1H, br.s).

MS (FAB) m/z: 529 (M+H)⁺.

Example 229 tert-Butyl2-{[((1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-{[(5-fluoroindol-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate

The title compound was obtained from the compound obtained inReferential Example 311 and the compound obtained in Referential Example406 in a similar manner to the process described in Example 226.

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 1.60-2.40 (6H, m), 2.80-3.20 (7H, m),4.15-4.25 (1H, m), 4.55-4.80 (5H, m), 6.84-6.87 (1H, m), 7.01 (1H, dt,J=2.4, 9.1 Hz), 7.25-7.30 (1H, m), 7.34 (1H, dd, J=9.1, 4.3 Hz),7.42-7.49 (1H, m), 7.70-7.80 (1H, m), 9.37-9.45 (1H, m).

MS (ESI) m/z: 599 (M+H)⁺.

Example 230N-{(1S,2R,4S)-2-[[(5,6-Dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}-4-[(dimethylamino)carbonyl]-5-fluoroindole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example229 in a similar manner to the process described in Example 227.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.65-1.90 (3H, m), 1.90-2.10 (2H,m), 2.80 (3H, s), 2.97 (3H, s), 2.98-3.15 (1H, m), 4.05-4.20 (1H, m),4.35-4.50 (2H, m), 4.58 (3H, br.s), 6.97-7.10 (2H, m), 7.35-7.47 (2H,m), 8.34 (1H, d, J=7.8 Hz), 8.41 (1H, d, J=8.1 Hz), 10.53 (2H, br.s),11.68 (1H, br.s).

MS (FAB) m/z: 499 (M+H)⁺.

Example 231N-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)-5-fluoroindole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example230 and formalin in a similar manner to the process described in Example18.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.65-1.90 (3H, m), 1.90-2.10 (2H,m), 2.80 (3H, s), 2.90-3.20 (7H, m), 4.05-4.20 (1H, m), 4.30-5.00 (5H,br.s), 6.95-7.10 (2H, m), 7.35-7.50 (2H, m), 8.33 (1H, d, J=7.6 Hz),8.41 (1H, d, J=8.1 Hz), 11.67 (1H, br.s), 12.37 (1H, br.s).

MS (FAB) m/z: 513 (M+H)⁺.

Example 232N-{(1R,2S,5S)-2-[(6-Chloro-2-naphthoyl)amino]-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 294 and the compound obtained in Referential Example293 in a similar manner to the process described in Example 226.

¹H-NMR (DMSO-d₆) δ: 1.48-1.56 (1H, m), 1.71-1.84 (3H, m), 1.95-2.04 (2H,m), 2.81 (3H, s), 3.00 (3H, s), 3.02 (3H, s), 3.06-3.15 (2H, m),4.13-4.14 (1H, m), 4.52-4.63 (4H, m), 7.60 (1H, d, J=8.5 Hz), 7.87 (1H,d, J=8.8 Hz), 7.96 (1H, d, J=8.5 Hz), 8.01 (1H, d, J=8.8 Hz), 8.10 (1H,s), 8.32 (1H, s), 8.45 (1H, d, J=8.1 Hz), 8.51 (1H, d, J=7.3 Hz).

MS (FAB) m/z: 540 (M+H)⁺.

Example 2337-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carboxamidehydrochloride and7-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carboxamide

A 4N dioxane solution (3.0 ml) of hydrochloric acid was added to asuspension of the compound (330 mg) obtained in Referential Example 299in a mixed solvent of dioxane (3.0 ml) and methylene chloride (3.0 ml),and the mixture was stirred at room temperature for 30 minutes. Thesolvent was distilled off under reduced pressure, and the thus-obtainedwhite powder was dissolved in N,N-dimethylformamide (5.0 ml), and thecompound (172 mg) obtained in Referential Example 293,1-hydroxybenzotriazole monohydrate (130 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg)were added to stir the mixture at room temperature for 15 hours. Thesolvent was distilled off under reduced pressure, methylene chloride anda saturated aqueous solution of sodium hydrogencarbonate were added tothe residue. The resultant organic layer was washed with saturatedsaline and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methylene chloride:methanol=20:1).A 1N ethanol solution (0.35 ml) of hydrochloric acid was added to asolution of the thus-obtained high-polar compound mainly formed inethanol (4.0 ml), and the solvent was distilled off under reducedpressure. Ethanol and diethyl ether were added to the residue, andprecipitate formed was collected by filtration to obtain7-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carboxamidehydrochloride (184 mg) a main product.

¹H-NMR (DMSO-d6) δ: 1.50-1.65 (1H, m), 1.70-1.90 (3H, m), 2.03-2.12 (1H,m), 2.15-2.30 (1H, m), 2.81 (3H, s), 2.90-3.05 (1H, m), 2.96 (3H, s),3.07 (3H, s), 4.28-4.37 (1H, m), 4.40-4.95 (5H, br), 8.02 (1H, d, J=8.8Hz), 8.38 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.91 (1H, s), 8.97 (1H, d,J=7.1 Hz), 9.43-9.57 (1H, br), 11.75-11.95 (0.5H, br), 12.35-11.55(0.5H, br).

MS (FAB) m/z: 542 (M+H)⁺.

In the purification by the column chromatography on silica gel,low-polar7-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carboxamide(98 mg) was also obtained as a by-product.

¹H-NMR (CDCl₃) δ: 1.90-2.25 (6H, m), 2.85-3.00 (1H, m), 2.95 (3H, s),3.05 (3H, s), 3.91 (3H, s), 4.43-4.54 (1H, m), 4.86-4.95 (1H, m), 6.70(1H, d, J=1.5 Hz), 7.19 (1H, d, J=1.5 Hz), 7.59 (1H, d, J=8.8 Hz), 7.76(1H, d, J=8.8 Hz), 7.95 (1H, d, J=8.8 Hz), 8.53 (1H, s), 8.64 (1H, d,J=8.0 Hz), 8.73 (1H, s).

MS (FAB) m/z: 540 (M+H)⁺.

Example 2347-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)isoquinoline-3-carboxamidehydrochloride

The compound (500 mg) obtained in Referential Example 146 was dissolvedin an ethanol solution (5 ml) of hydrochloric acid, and the mixture wasstirred at room temperature for 30 minutes. The solvent was distilledoff under reduced pressure, and the residue was dissolved inN,N-dimethylformamide (7 ml), and the compound (299 mg) obtained inReferential Example 293, 1-hydroxybenzotriazole monohydrate (71 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (403 mg)were added to the solution to stir the mixture at room temperature for anight. The solvent was distilled off under reduced pressure, a saturatedaqueous solution of sodium hydrogencarbonate and methylene chloride wereadded to the residue to conduct liquid separation. The resultant waterlayer was extracted with methylene chloride. Organic layers werecombined and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methylene chloride:methanol=93:7)to obtain a free base (260 mg) of the title compound as a pale yellowsolid. This product was dissolved in methylene chloride, a 1N ethanolsolution (961 μl) of hydrochloric acid was added, and the solvent wasdistilled off under reduced pressure. A small amount of methanol wasadded to the residue, and diethyl ether was added dropwise to collectprecipitate formed by filtration. This product was washed with diethylether to obtain the title compound (260 mg).

¹H-NMR (DMSO-d₆) δ: 1.47-1.56 (1H, m), 1.71-1.75 (3H, m), 1.95-1.99 (1H,m), 2.12-2.15 (1H, m), 2.78 (3H, s), 2.95 (3H, s), 2.98 (1H, br.s), 3.05(3H, s), 4.19-4.22 (1H, m), 4.44-4.52 (3H, m), 4.74-4.88 (2H, m), 7.87(1H, dd, J=8.8, 1.7 Hz), 8.24 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=1.7 Hz),8.58 (1H, s), 8.90-8.92 (2H, m), 9.30 (1H, s), 12.65-12.75 (1H, m).

MS (FAB) m/z: 541 (M+H)⁺.

Example 235 tert-Butyl2-[({(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate

The compound (95.4 mg) obtained in Referential Example 316 was dissolvedin diethyl ether (1 ml) in an argon atmosphere, and tert-butyllithium(1.60N pentane solution, 244 μl) was added dropwise at −78° C. After themixture was stirred for 1 hour at −78° C., carbon dioxide was blown intothe reaction mixture for 10 minutes. The reaction mixture was heated toroom temperature. After the reaction mixture was concentrated underreduced pressure, the residue was dissolved in N,N-dimethylformamide (5ml). To the solution, were successively added the compound (178 mg)obtained in Referential Example 432, 1-hydroxybenzotriazole monohydrate(48.0 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (136 mg). The resultant mixture was stirred overnight atroom temperature. The reaction mixture was concentrated, and methylenechloride and a saturated aqueous solution of sodium hydrogencarbonatewere added to the residue to separate an organic layer. The organiclayer was dried over anhydrous sodium sulfate, and the solvent was thendistilled off under reduced pressure. The resultant residue was purifiedby column chromatography on silica gel (methanol:methylenechloride=1:19) to obtain the title compound (140 mg).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 1.52 (3H, s), 1.54 (3H, s), 1.70-2.10(4H, m), 2.15-2.45 (2H, m), 2.80-3.20 (9H, m), 4.10-4.25 (1H, br),4.60-4.75 (3H, m), 6.85 (1H, br.s), 7.21 (1H, dd, J=8.8, 1.8 Hz), 7.34(1H, d, J=8.8 Hz), 7.48 (1H, d, J=7.3 Hz), 7.61-7.63 (1H, m), 7.89 (1H,br.s), 9.27 (1H, br.s).

MS (ESI) m/z: 657 (M+H)⁺.

Example 236N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained in Example235 in a similar manner to the process described in Example 227.

¹H-NMR (DMSO-d₆) δ: 1.40 (6H, s), 1.45-1.60 (1H, m), 1.70-2.05 (5H, m),2.81 (3H, s), 2.95-3.15 (6H, m), 4.05-4.20 (1H, br), 4.25-4.45 (2H, m),4.55-4.65 (1H, m), 7.06 (1H, d, J=1.7 Hz), 7.17 (1H, dd, J=8.8, 2.0 Hz),7.42 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=2.0 Hz), 8.34-8.39 (2H, m), 9.77(1H, br.s), 9.84 (1H, br.s), 11.79 (1H, br.s).

MS (ESI) m/z: 557 (M+H)⁺.

Example 237 tert-Butyl2-[({(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

The compound (1.27 g) obtained in Referential Example 50 was dissolvedin tetrahydrofuran (48 ml), and lithium hydroxide (117 mg) and water(6.0 ml) were added to stir the mixture at room temperature for 4.5hours. The reaction mixture was dried to solid under reduced pressure toobtain a crude carboxylic acid lithium salt (1.24 g). This product wascondensed with the compound obtained in Referential Example 432 in asimilar manner to the process described in the step 2) of Example 226 toobtain the title compound.

¹H-NMR (CDCl₃) δ: 1.50-1.70 (1H, m), 1.54 (9H, s), 1.80-2.10 (3H, m),2.25-2.50 (2H, m), 2.85-2.95 (1H, m), 2.99 (3H, s), 3.14 (3H, s),4.15-4.25 (1H, m), 4.65-4.75 (1H, m), 4.80-4.90 (4H, m), 6.97 (1H, s),7.15-7.25 (1H, m), 7.30-7.40 (1H, m), 7.60-7.65 (1H, m), 8.15-8.25 (1H,m), 8.40-8.45 (1H, m), 8.75-8.85 (1H, m), 9.40-9.45 (1H, m).

MS (ESI) m/z: 611 (M+H)⁺.

Example 238N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carboxamidehydrochloride

The compound (367 mg) obtained in Example 237 was dissolved in methylenechloride (10 ml), and trifluoroacetic acid (10 ml) was added to stir themixture at room temperature for 2 hours. The reaction mixture was driedto solid under reduced pressure. The title compound was obtained fromthe thus-obtained crude product and formalin in a similar manner to theprocess described in Example 18.

¹H-NMR (DMSO-d6) δ: 1.50-1.60 (1H, m), 1.65-2.10 (5H, m), 2.81 (3H, s),2.90-3.00 (1H, m), 2.96 (3H, s), 3.05 (3H, s), 4.10-4.20 (1H, m),4.55-4.65 (1H, m), 4.65-4.90 (4H, br), 7.06 (1H, s), 7.15 (1H, dd,J=8.7, 2.1 Hz), 7.41 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=1.7 Hz),8.35-8.45 (1H, m), 8.57 (1H, d, J=8.1 Hz), 9.00 (1H, s), 11.80 (1H, s),11.90-12.20 (1H, m).

MS (FAB) m/z: 524 (M+H)⁺.

Example 2397-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(6-methyl-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl)carbonyl]amino}cyclohexyl)isoquinoline-3-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 146 with an ethanol solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example322 in a similar manner to the process described in Example 49.

¹H-NMR (DMSO-d₆) δ: 1.50-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.15 (2H,m), 2.81 (3H, s), 2.95 (3H, s), 2.90-3.05 (1H, m), 3.26 (3H, s),4.20-4.55 (2H, m), 5.00 (2H, s), 7.91 (1H, d, J=8.8 Hz), 8.27 (1H, d,J=8.8 Hz), 8.37 (1H, s), 8.54 (1H, s), 8.62 (1H, s), 8.79 (1H, d, J=8.3Hz), 8.94 (1H, d, J=8.1 Hz), 9.32 (1H, s).

MS (ESI) m/z: 554 (M+H)⁺.

Example 2407-Chloro-N-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)isoquinoline-3-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 325 and the compound obtained in Referential Example10 in a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 0.98, 1.04 (3H, each t, J=7.1 Hz), 1.52-1.60 (1H,m), 1.74-1.77 (3H, m), 1.96-2.05 (1H, m), 2.15-2.18 (1H, m), 2.77-2.93(8H, m), 3.17-3.32 (3H, m), 3.49 (1H, br.s), 4.22 (1H, br.s), 4.41-4.45(1H, m), 4.51 (1H, br.s), 4.69-4.72 (1H, m), 7.89 (1H, d, J=8.7 Hz),8.26 (1H, d, J=8.7 Hz), 8.37 (1H, s), 8.60 (1H, s), 8.91-8.98 (2H, m),9.32 (1H, d, J=6.6 Hz), 11.39, 11.53 (1H, each m).

MS (FAB) m/z: 569 (M+H)⁺.

Example 241N-{(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[2-(dimethylamino)-2-oxoethyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 336 and the compound obtained in Referential Example10 in a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.13-1.22 (1H, m), 1.40-1.46 (1H, m), 1.68-1.99 (5H,m), 2.18-2.29 (2H, m), 2.80 (3H, s), 2.92 (3H, s), 2.96 (3H, s), 3.22(2H, br.s), 3.49 (1H, br.s), 3.70 (1H, br.s), 4.09-4.16 (1H, m),4.42-4.46 (2H, m), 4.67 (1H, br.s), 7.03 (1H, s), 7.16 (1H, dd, J=8.5,1.5 Hz), 7.42 (1H, d, J=8.5 Hz), 7.67 (1H, s), 8.01 (1H, d, J=8.5 Hz),8.40 (1H, d, J=7.8 Hz), 11.35-11.58 (1H, m), 11.76 (1H, br.s).

MS (FAB) m/z: 557 (M+H)⁺.

Example 242N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(methylsulfonyl)methyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 340 with an ethanol solution of hydrochloric acidand then condensing it with the compound obtained in Referential Example10 in a similar manner to the process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.35-1.40 (1H, m), 1.55-1.62 (1H, m), 1.70-1.76 (1H,m), 1.88-1.94 (1H, m), 2.03-2.07 (1H, m), 2.13-2.17 (1H, m), 2.30-2.33(1H, m), 2.43-3.48 (10H, m), 3.60-3.73 (2H, m), 4.11-4.16 (1H, m),4.40-4.42 (2H, m), 4.68-4.73 (1H, m), 7.05 (1H, s), 7.16 (1H, dd, J=2.0,8.8 Hz), 7.41 (1H, d, J=8.8 Hz), 7.68 (1H, s), 8.26 (1H, d, J=7.8 Hz),8.39 (1H, d, J=7.8 Hz), 11.78 (1H, br.s).

MS (ESI) m/z: 564 (M+H)⁺.

Example 243N-{(1R,2S,5S)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained by hydrogenation of the compoundobtained in Referential Example 252 and then condensing it with thecompound obtained in Referential Example 345 in a similar manner to theprocess described in Example 223.

¹H-NMR (CDCl₃) δ: 1.56-1.66 (1H, m), 1.76-1.93 (2H, m), 2.02-2.06 (1H,m), 2.19-2.26 (1H, m), 2.30-2.34 (1H, m), 2.52 (3H, s), 2.79-2.88 (3H,m), 2.91-2.94 (2H, m), 2.96 (3H, s), 3.09 (3H, s), 3.69-3.77 (2H, m),4.13-4.19 (1H, m), 4.58-4.61 (1H, m), 6.72 (1H, s), 6.84 (1H, s), 7.50(1H, d, J=7.3 Hz), 7.60 (1H, d, J=5.8 Hz), 10.54 (1H, br).

MS (ESI) m/z: 549 (M+H)⁺.

Example 244N-{(1R,2S,5S)-2-{[3-(4-Chlorophenyl)-2-propynoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by hydrogenation of the compoundobtained in Referential Example 252 and then condensing it with thecompound obtained in Referential Example 347 in a similar manner to theprocess described in Example 223.

¹H-NMR (DMSO-d₆) δ: 1.38-1.50 (1H, m), 1.58-1.92 (4H, m), 2.78 (3H, s),2.90 (3H, s), 2.97 (3H, s), 3.01-3.24 (3H, m), 3.26-3.80 (2H, m),3.90-3.98 (1H, m), 4.30-4.78 (3H, m), 7.51 (1H, d, J=8.8 Hz), 7.57 (1H,d, J=8.8 Hz), 8.34 (1H, d, J=8.8 Hz), 8.83 (1H, d, J=7.8 Hz).

MS (FAB) m/z: 528 (M+H)⁺.

Example 2456-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-oxo-1,4-dihydroquinazoline-2-carboxamidehydrochloride

The title compound was obtained by hydrogenation of the compoundobtained in Referential Example 252 and then condensing it with thecompound obtained in Referential Example 349 in a similar manner to theprocess described in Example 223.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.20 (3H,m), 2.80 (3H, s), 2.93 (3H, s), 2.97 (3H, s), 2.98-3.80 (4H, m),4.05-4.20 (2H, m), 4.35-4.80 (3H, m), 7.63 (1H, d, J=8.3 Hz), 7.90 (1H,d, J=7.3 Hz), 8.75-9.00 (2H, m), 11.00-11.50 (1H, br), 12.53 (1H, br.s).

MS (ESI) m/z: 573 (M+H)⁺.

Example 246N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-oxoethanethioyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (184 mg) obtained in Referential Example 253 and thecompound (150 mg) obtained in Referential Example 351 were dissolved ina mixed solvent of methanol (1 ml)-methylene chloride (4 ml), thesolution was heated and stirred at 150° C., and the heating wascontinued for 5 minutes after distilling off the solvent. After thereaction mixture was allowed to cool, the formed product was purified bycolumn chromatography on silica gel (methylene chloride:methanol=24:1)to obtain the title compound (59 mg).

¹H-NMR (CDCl₃) δ: 1.65-1.90 (2H, m), 1.90-2.00 (1H, m), 2.00-2.15 (2H,m), 2.20-2.30 (1H, m), 2.52 (3H, s), 2.75-2.95 (5H, m), 2.96 (3H, s),3.07 (3H, s), 3.68 (1H, d, J=15.2 Hz), 3.75 (1H, d, J=15.7 Hz),4.45-4.60 (1H, m), 4.80-4.85 (1H, m), 7.31 (2H, d, J=8.8 Hz), 7.44 (1H,d, J=8.6 Hz), 7.60 (2H, d, J=8.8 Hz), 9.99 (1H, d, J=7.6 Hz), 10.15 (1H,s).

MS (ESI) m/z: 563 (M+H)⁺.

Example 247N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (184 mg) obtained in Referential Example 253 and thecompound (150 mg) obtained in Referential Example 353 were dissolved ina mixed solvent of methanol (0.3 ml)-methylene chloride (0.3 ml), thesolution was heated and stirred at 150° C., and the heating wascontinued for 5 minutes after distilling off the solvent. reactionmixture was allowed to cool, the formed product was purified by columnchromatography on silica gel (methylene chloride:methanol=24:1) toobtain the title compound (52 mg).

¹H-NMR (CDCl₃) δ: 1.60-2.00 (3H, m), 2.00-2.20 (2H, m), 2.25-2.40 (1H,m), 2.53 (3H, s), 2.80-2.95 (5H, m), 2.96 (3H, s), 3.08 (3H, s), 3.70(1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.45-4.60 (1H, m),4.75-4.85 (1H, m), 7.45 (1H, d, J=8.3 Hz), 7.67 (1H, dd, J=8.8, 2.5 Hz),8.18 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=2.0 Hz), 10.06 (1H, d, J=6.3 Hz),10.56 (1H, s).

MS (ESI) m/z: 564 (M+H)⁺.

Example 248N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-thioxoacetyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (72 mg) obtained in Referential Example 355 and2-amino-5-chloropyridine (100 mg) were dissolved in a mixed solvent ofmethanol (0.2 ml)-methylene chloride (0.2 ml), the solution was heatedand stirred at 150° C., and the heating was continued for 8 minutesafter distilling off the solvent. After the reaction mixture was allowedto cool, the formed product was purified by preparative thin-layerchromatography on silica gel (methylene chloride:methanol=23:2) toobtain the title compound (4 mg).

¹H-NMR (CDCl₃) δ: 1.60-2.00 (3H, m), 2.00-2.20 (3H, m), 2.53 (3H, s),2.75-3.00 (5H, m), 2.95 (3H, s), 3.05 (3H, s), 3.65-3.80 (2H, m),4.05-4.15 (1H, m), 4.70-4.80 (1H, m), 7.28 (1H, d), 7.43 (1H, d, J=9.3Hz), 7.75 (1H, dd, J=8.8, 2.7 Hz), 8.41 (1H, d, J=2.7 Hz), 9.05 (1H, d,J=8.8 Hz), 11.56 (1H, s).

MS (ESI) m/z: 564 (M+H)⁺.

Example 249N¹-(5-Chloro-2-thienyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 356, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.40-1.55 (1H, m), 1.60-1.85 (3H, m), 1.90-2.15 (2H,m), 2.79 (3H, s), 2.90-3.15 (1H, m), 2.92 (3H, s), 2.94 (3H, s),3.15-3.30 (2H, m), 3.50-3.80 (2H, m), 3.95-4.05 (1H, m), 4.35-4.90 (3H,m), 6.90 (1H, d, J=4.2 Hz), 6.94 (1H, d, J=4.2 Hz), 8.72 (1H, d, J=7.3Hz), 9.13 (1H, br.s), 11.21 (1H, br.s), 12.32 (1H, br.s).

MS (ESI) m/z: 553 (M+H)⁺.

Example 250N-{(1R,2S,5S)-2-{[(4-Chloroanilino)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

4-Chlorophenyl isocyanate (76.8 mg) was added to a solution of thecompound (183 mg) obtained in Referential Example 253 in methylenechloride (20 ml), and the mixture was stirred at room temperature for 24hours. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=20:1→10:1) to distil off the solvent. The residue wasdissolved in ethanol (2 ml) and methylene chloride (2 ml), a 1N ethanolsolution (0.4 ml) of hydrochloric acid was added to stir the mixture atroom temperature for 30 minutes. The reaction mixture was concentratedunder reduced pressure, and the residue was solidified with diethylether to obtain the title compound (160 mg).

¹H-NMR (DMSO-d₆) δ: 1.35-1.50 (1H, m), 1.60-1.90 (5H, m), 2.79 (3H, s),2.92 (3H, s), 3.00 (3H, s), 3.10-3.60 (4H, m), 3.60-3.90 (2H, m),4.35-4.80 (3H, m), 6.26 (1H, br.s), 7.23 (2H, d, J=9.0 Hz), 7.37 (2H, d,J=9.0 Hz), 8.53 (1H, br.s), 8.72 (1H, br.s), 11.35, 11.67 (total 1H,each s).

MS (ESI) m/z: 519 (M+H)⁺.

Example 251N¹-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexyl)-N²-(5-fluoropyridin-2-yl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 357, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.47-1.53 (1H, m), 1.68-1.75 (3H, m), 1.99-2.10 (2H,m), 2.80 (3H, s), 2.80-3.00 (1H, m), 2.95 (6H, s), 3.18-3.21 (2H, m),3.40-3.80 (2H, m), 3.87-4.82 (4H, m), 7.82-7.85 (1H, m), 8.01-8.05 (1H,m), 8.40 (1H, d, J=2.9 Hz), 8.71 (1H, d, J=7.7 Hz), 9.13 (1H, d, J=7.3Hz), 10.27 (1H, s).

MS (FAB) m/z: 532 (M+H)⁺.

Example 252N¹-(4-Chlorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 242 and the compound obtained in Referential Example272 in a similar manner to the process described in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.47-1.51 (1H, m), 1.69-1.75 (3H, m), 1.98-2.05 (2H,m), 2.80 (3H, s), 2.95 (3H, s), 2.98-3.04 (1H, m), 3.10 (3H, s),3.40-4.61 (6H, m), 7.41 (2H, d, J=8.8 Hz), 7.81 (2H, d, J=8.8 Hz), 8.76(1H, d, J=7.6 Hz), 8.95 (1H, d, J=8.3 Hz), 10.79 (1H, s).

MS (FAB) m/z: 533 (M+H)⁺.

Example 253N¹-[4-Chloro-2-(trifluoromethyl)phenyl]-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

Thionyl chloride (1 ml) was added to a chloroform solution (10 ml) ofthe compound (269 mg) obtained in Referential Example 359, and themixture was stirred at 75° C. for 30 minutes. The solvent was distilledoff under reduced pressure, and the residue was dried. To the residuewere added a methylene chloride solution (7 ml) of the compound (286 mg)obtained in Referential Example 253 and pyridine (3 ml) under icecooling. The mixture was stirred for 2 hours while the temperature ofthe system was raised to room temperature. A saturated aqueous solution(10 ml) of sodium hydrogencarbonate was added to the reaction mixture toconduct liquid separation. The resultant organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the resultant residue was subjected to columnchromatography on silica gel (methylene chloride:methanol=20:1) andcolumn chromatography on LH-20 (molecular sieve, methanol) to obtain afree base (90 mg) of the title compound as a pale yellow amorphoussolid. Methylene chloride (5 ml), ethanol (5 ml) and a 1N ethanolsolution (1 ml) of hydrochloric acid were added to the product, anddistilling-off and drying were conducted under reduced pressure toobtain the title compound.

¹H-NMR (DMSO-d₆) δ: 1.41-1.55 (1H, m), 1.59-1.80 (3H, m), 1.98-2.13 (2H,m), 2.77 (3H, s), 2.91 (6H, s), 3.12-3.26 (2H, m), 3.30-3.58 (2H, m),3.60-3.78 (1H, m), 3.94-4.04 (1H, m), 4.35-4.63 (2H, m), 4.64-4.80 (1H,m), 7.73-7.82 (2H, m), 7.85 (1H, s), 8.68-8.73 (1H, m), 9.18 (1H, br.s),10.31 (1H, s).

MS (ESI) m/z: 615 (M+H)

Example 254N¹-{4-Chloro-2-[(dimethylamino)carbonyl]phenyl}-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 362, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.42-1.56 (1H, m), 1.59-1.82 (3H, m), 1.98-2.14 (2H,m), 2.79 (3H, s), 2.91 (3H, s), 2.93 (3H, s), 2.95 (3H, s), 2.98 (3H,s), 3.10-3.30 (4H, m), 3.62-3.79 (1H, m), 3.92-4.01 (1H, m), 4.34-4.50(2H, m), 4.66-4.79 (1H, m), 7.52 (1H, d, J=2.4 Hz), 7.55 (1H, dd, J=2.4,8.5 Hz), 8.05 (1H, d, J=8.5 Hz), 8.75 (1H, br), 9.10-9.24 (1H, m), 10.52(1H, s).

MS (ESI) m/z: 618 (M+H)⁺.

Example 255N¹-[4-Chloro-2-(hydroxymethyl)phenyl]-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 270 with 4-chloro-2-hydroxymethylaniline and thentreating the condensation product with hydrochloric acid in a similarmanner to the process described in Example 199.

¹H-NMR (DMSO-d₆) δ: 1.42-1.57 (1H, m), 1.58-1.81 (3H, m), 1.98-2.14 (2H,m), 2.79 (3H, s), 2.93 (6H, s), 3.12-3.58 (4H, m), 3.67-3.80 (1H, m),3.94-4.04 (1H, m), 4.37-4.50 (1.5H, m), 4.55 (2H, s), 4.67-4.80 (1H, m),5.77-5.92 (0.5H, m), 7.37 (1H, dd, J=2.4, 8.6 Hz), 7.42 (1H, d, J=2.4Hz), 7.91 (1H, d, J=8.6 Hz), 8.74-8.81 (1H, m), 9.03-9.19 (1H, m), 10.79(1H, s).

MS (ESI) m/z: 577 (M+H)⁺.

Example 256N¹-(4-Chloro-2-methoxyphenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 364, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.40-1.55 (1H, m), 1.58-1.79 (3H, m), 1.94-2.11 (2H,m), 2.77 (3H, s), 2.92 (6H, s), 3.05-3.55 (4H, m), 3.65-3.75 (1H, br),3.90 (3H, s), 3.91-4.00 (1H, m), 4.36-4.47 (2H, br), 4.65-4.77 (1H, br),7.04 (1H, dd, J=8.5, 2.0 Hz), 7.20 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=8.5Hz), 8.65-8.80 (1H, br), 9.10-9.25 (1H, br), 9.74 (1H, s), 11.10-11.35(1H, br).

MS (ESI) m/z: 577 (M+H)⁺.

Example 257N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-(hydroxyimino)acetyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by deprotecting the compound obtained inReferential Example 366 by hydrochloric acid treatment, condensing thedeprotected compound with the compound obtained in Referential Example10 and then treating the condensation product with hydrochloric acid ina similar manner to the process described in Example 214.

¹H-NMR (DMSO-d₆) δ: 1.41-1.53 (1H, m), 1.57-1.77 (3H, m), 1.88-2.04 (2H,m), 2.77 (3H, s), 2.91 (6H, s), 3.00-3.60 (4H, m), 3.65-3.74 (1H, br),3.87-3.96 (1H, m), 4.37-4.48 (2H, m), 4.66-4.76 (1H, m), 6.70 (2H, d,J=8.8 Hz), 7.04 (1H, d, J=8.8 Hz), 7.10 (1H, d, J=8.8 Hz), 8.40-8.53(2H, m), 8.57-8.66 (1H, m), 10.66-10.76 (1H, br), 10.30-10.47 (1H, br).

MS (ESI) m/z: 562 (M+H)⁺.

Example 258N¹-(4-Chlorophenyl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamidehydrochloride

The title compound was obtained by deprotecting the compound obtained inReferential Example 367 by hydrochloric acid treatment, condensing thedeprotected compound with the compound obtained in Referential Example10 and then treating the condensation product with hydrochloric acid ina similar manner to the process described in Example 214.

¹H-NMR (DMSO-d₆) δ: 1.60-1.72 (1H, m), 1.99-2.22 (1H, m), 2.90 (3H, s),3.03-4.80 (17H, m), 7.40 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz),8.56-8.73 (1H, br), 9.14-9.33 (1H, br), 10.83 (1H, s), 11.20-11.55 (1H,br).

MS (ESI) m/z: 549 (M+H)⁺.

Example 259N¹-(5-Chloropyridin-2-yl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamidehydrochloride

The title compound was obtained by deprotecting the compound obtained inReferential Example 368 by hydrochloric acid treatment, condensing thedeprotected compound with the compound obtained in Referential Example10 and then treating the condensation product with hydrochloric acid ina similar manner to the process described in Example 214.

¹H-NMR (DMSO-d₆) δ: 1.60-1.72 (1H, m), 1.98-2.20 (1H, m), 2.90 (3H, s),3.00-4.77 (17H, m), 7.20-7.35 (0.8H, br), 7.48-7.56 (0.2H, br),7.94-8.07 (1H, br), 8.40-8.70 (1H, br), 8.48-8.70 (1H, br), 9.23-9.45(1H, br), 10.21-10.35 (1H, br), 11.30-11.70 (1H, br).

MS (ESI) m/z: 550 (M+H)⁺.

Example 260N¹-(5-Bromopyridin-2-yl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamidehydrochloride

The title compound was obtained by deprotecting the compound obtained inReferential Example 369 by hydrochloric acid treatment, condensing thedeprotected compound with the compound obtained in Referential Example10 and then treating the condensation product with hydrochloric acid ina similar manner to the process described in Example 214.

¹H-NMR (DMSO-d₆) δ: 1.60-1.73 (1H, m), 1.97-2.20 (1H, m), 2.90 (3H, s),3.03-3.52 (7H, m), 3.64-4.07 (5H, m), 4.10-4.50 (4H, m), 4.65-4.78 (1H,m), 7.28-7.35 (0.2H, m), 7.97 (1H, d, J=8.8 Hz), 8.11 (1H, dd, J=8.8,2.2 Hz), 8.51 (1H, d, J=2.2 Hz), 8.55-8.67 (1H, m), 9.22-9.41 (1H, m),10.20-10.31 (0.8H, m), 11.25-11.70 (1H, br).

MS (ESI) m/z: 594 (M+H)⁺.

Example 261N¹-(4-Chlorophenyl)-N³-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)malonamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 371 with the compound obtained in ReferentialExample 253 and then treating the condensation product with hydrochloricacid in a similar manner to the process described in Example 5.

¹H-NMR (DMSO-d₆) δ: 1.32-1.50 (1H, m), 1.55-1.87 (5H, m), 2.78 (3H, m),2.92 (3H, s), 2.98 (3H, s), 2.99-3.00 (1H, m), 3.05-3.50 (5H, m),3.65-3.75 (1H, m), 3.80-3.92 (1H, m), 4.35-4.45 (1H, m), 4.45-4.55 (1H,m), 4.65-4.80 (1H, m), 7.34 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz),8.00-8.10 (1H, m), 8.30-8.40 (1H, m), 10.29 (1H, d, J=12.5 Hz), 12.40(1H, br.s)

MS (FAB) m/z: 561 (M+H)⁺.

Example 262N¹-(3-Chlorophenyl)-N³-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)malonamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 373 with the compound obtained in ReferentialExample 253 and then treating the condensation product with hydrochloricacid in a similar manner to the process described in Example 5.

¹H-NMR (DMSO-d₆) δ: 1.32-1.50 (1H, m), 1.55-1.90 (5H, m), 2.77 (3H, s),2.91 (3H, s), 2.98 (3H, s), 2.99-3.00 (1H, m), 3.05-3.50 (5H, m),3.65-3.80 (1H, m), 3.80-3.90 (1H, m), 4.35-4.50 (1H, m), 4.50-4.60 (1H,m), 4.65-4.80 (1H, m), 7.09 (1H, d, J=8.8 Hz), 7.31 (1H, d, J=8.8 Hz),7.38 (1H, t, J=8.8 Hz), 7.79 (1H, s), 8.00-8.10 (1H, m), 8.30-8.40 (1H,m), 10.28 (1H, d, J=12.5 Hz), 11.67 (1H, br.s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 263N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

10% Palladium on carbon (0.3 g) was added to a solution of the compound(0.33 g) obtained in Referential Example 404 in ethanol (20 ml), and themixture was stirred at room temperature for 24 hours under a hydrogenatmosphere. After removing insoluble matter by filtration through Celitepad, the filtrate was concentrated under reduced pressure. The resultantresidue (0.37 g) was dissolved in N,N-dimethylformamide (20 ml), and thecompound (0.3 g) obtained in Referential Example 266,1-hydroxybenzotriazole monohydrate (0.2 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.37 g)were successively added to stir the mixture at room temperature for 18hours. The reaction mixture was concentrated under reduced pressure, andthe resultant residue was diluted with a mixed solvent ofchloroform-methanol (9:1) and washed with a saturated aqueous solutionof sodium hydrogencarbonate and saturated aqueous solution of sodiumchloride. After the resultant organic layer was dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure, the resultant residue was purified by column chromatography onsilica gel (chloroform:methanol=95:5) to concentrate the intendedfraction. A 1N ethanol solution of hydrochloric acid was added to form ahydrochloride. This salt was recrystallized from a mixed solvent ofmethanol and diethyl ether to obtain the title compound (0.28 g).

¹H-NMR (DMSO-d₆) δ: 0.95 (1.5H, t, J=6.9 Hz), 1.42 (1.5H, t, J=6.9 Hz),1.40-1.52 (1H, m), 1.60-1.78 (3H, m), 1.92-2.11 (2H, m), 2.74 (3H, s),2.90 (3H, s), 3.10-3.38 (5H, m), 3.40-3.52 (1H, m), 3.68-3.70 (1H, m),3.96-4.05 (1H, m), 4.41 (2H, s), 4.70 (1H, d, J=15.9 Hz), 8.00-8.01 (2H,m), 8.44 (1H, s), 8.71 (1H, dd, J=10.1, 2.2 Hz), 9.14 (0.5H, d, J=7.8Hz), 9.22 (0.5H, d, J=8.3 Hz), 10.24 (0.5H, s), 10.28 (0.5H, s), 11.48(1H, br.s), 11.61 (1H, br.s).

MS (FAB) m/z: 562 (M+H)⁺.

Example 264N¹-(4-Chlorophenyl)-N²-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by converting the compound obtained inReferential Example 404 into an amine, condensing the amine with thecompound obtained in Referential Example 374 and then treating thecondensation product with hydrochloric acid in a similar manner to theprocess described in Example 263.

¹H-NMR (DMSO-d₆) δ: 0.97 (1.5H, t, J=6.9 Hz), 1.04 (1.5H, t, J=6.9 Hz),1.40-1.60 (1H, m), 1.60-1.80 (3H, m), 1.92-2.11 (2H, m), 2.74 (3H, s),2.89 (3H, s), 3.10-3.32 (5H, m), 3.40-3.52 (1H, m), 3.65-3.80 (1H, m),3.90-4.05 (1H, m), 4.40 (2H, s), 4.70 (1H, d, J=15.9 Hz), 7.39 (2H, d,J=8.8 Hz), 7.82 (2H, d, J=8.8 Hz), 8.75 (1H, dd, J=10.1, 2.2 Hz), 9.00(0.5H, d, J=7.8 Hz), 9.08 (0.5H, d, J=8.3 Hz), 10.81 (1H, d, J=4.9 Hz),11.45 (1H, br.s).

MS (FAB) m/z: 561 (M+H)⁺.

Example 265N¹-(5-Bromopyridin-2-yl)-N²-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by converting the compound obtained inReferential Example 404 into an amine, condensing the amine with thecompound obtained in Referential Example 375 and then treating thecondensation product with hydrochloric acid in a similar manner to theprocess described in Example 263.

¹H-NMR (DMSO-d₆) δ: 1.02 (1.5H, t, J=6.9 Hz), 1.08 (1.5H, t, J=6.9 Hz),1.49-1.60 (1H, m), 1.60-1.86 (3H, m), 2.00-2.20 (2H, m), 2.81 (3H, s),2.97 (3H, s), 3.15-3.42 (6H, m), 3.50-3.60 (1H, m), 3.70-3.82 (1H, m),4.48 (2H, s), 4.77 (1H, d, J=15.9 Hz), 8.04 (1H, d, J=8.8 Hz), 8.17 (1H,d, J=8.8 Hz), 8.58 (1H, s), 8.78 (1H, dd, J=10.1, 2.2 Hz), 9.21 (0.5H,d, J=7.8 Hz), 9.29 (0.5H, d, J=8.3 Hz), 10.29 (0.5H, s), 10.33 (0.5H,s), 11.53 (0.5H, br.s), 11.65 (0.5H, br.s).

MS (FAB) m/z: 607 (M+H)⁺.

Example 266N¹-(4-chloro-3-fluorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by converting the compound obtained inReferential Example 252 into an amine, condensing the amine with thecompound obtained in Referential Example 378 and then treating thecondensation product with hydrochloric acid in a similar manner to theprocess described in Example 263.

¹H-NMR (DMSO-d₆) δ: 1.44-1.52 (1H, m), 1.65-1.76 (3H, m), 2.01-2.07 (2H,m), 2.77 (3H, s), 2.93 (6H, s), 2.94-3.00 (1H, m), 3.10-3.38 (3H, m),3.68-3.70 (1H, m), 3.96-4.05 (1H, m), 4.42 (2H, s), 4.70 (1H, d, J=15.9Hz), 7.56 (1H, t, J=8.8 Hz), 7.68 (1H, d, J=8.8 Hz), 7.90 (1H, dd,J=11.7, 1.5 Hz), 8.73 (1H, dd, J=12.5, 7.3 Hz), 9.06 (1H, dd, J=12.5,8.1 Hz), 11.01 (1H, d, J=5.8 Hz), 11.30-11.42 (1H, m).

MS (FAB) m/z: 565 (M+H)⁺.

Example 267N-{(1R,2S,5S)-2-{[3-(4-Chlorophenyl)-3-oxopropanoyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The title compound was obtained by deprotecting the compound obtained inReferential Example 383 by hydrochloric acid treatment, condensing thedeprotected compound with the compound obtained in Referential Example10 and then treating the condensation product with hydrochloric acid ina similar manner to the process described in Example 214.

¹H-NMR (CDCl₃) (free base) δ: 1.22-1.32 (1H, m), 1.49-1.92 (3H, m),1.95-2.10 (2H, m), 2.53 (3H, s), 2.70-2.79 (1H, m), 2.80-2.90 (2H, m),2.93 (6H, s), 2.95-3.09 (2H, m), 3.72 (2H, s), 3.87 (2H, s), 4.05-4.19(1H, m), 4.60-4.70 (1H, m), 7.20-7.40 (2H, m), 7.42 (2H, d, J=8.3 Hz),7.87 (2H, d, J=8.3 Hz).

MS (FAB) m/z: 546 (M+H)⁺.

Example 268N¹-(5-Chloropyridin-2-yl)-N²-((1R,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamide

The title compound was obtained by deprotecting the compound obtained inReferential Example 386 by hydrochloric acid treatment, and condensingthe deprotected compound with the compound obtained in ReferentialExample 293 in a similar manner to the process described in Example 214.

¹H-NMR (DMSO-d₆) δ: 1.00-2.35 (7H, m), 2.96 (3H, s), 3.04 (3H, s),3.85-3.95 (1H, m), 3.88 (3H, s), 4.60-4.75 (1H, m), 6.68 (1H, d, J=2.0Hz), 7.17 (1H, d, J=2.0 Hz), 7.20-7.32 (1H, m), 7.67 (1H, dd, J=8.8, 2.8Hz), 7.99 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=8.8 Hz), 8.25 (1H, d, J=2.8Hz), 9.64 (1H, s).

HRMS (FAB) m/z: 532.1520 (M+H)⁺.

(Calculated; C₂₃H₂₇ClN₇O₄S: 532.1534).

Example 269N¹-[(5-Chloropyridin-2-yl)amino]-N²-((1R,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by reducing the compound obtained inReferential Example 387 in a similar manner to the process described inReferential Example 253, and condensing the reduction product with thecompound obtained in Referential Example 266 and treating thecondensation product with hydrochloric acid in a similar manner to theprocess described in Example 208.

¹H-NMR (DMSO-d₆) δ: 1.50-1.98 (6H, m), 2.82 (3H, s), 2.91 (3H, s), 2.95(3H, s), 2.86-3.92 (7H, m), 4.30-4.81 (2H, m), 7.92-8.09 (2H, m),8.39-8.47 (1H, m), 8.56-8.72 (2H, m), 10.17 (1H, s).

MS (ESI) m/z: 548 (M+H)⁺.

Example 270N¹-(4-Chlorophenyl)-N²-((1R,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide

The title compound was obtained by reducing the compound obtained inReferential Example 387 in a similar manner to the process described inReferential Example 253, and condensing the reduction product with thelithium salt obtained by hydrolyzing the compound obtained inReferential Example 242 and treating the condensation product withhydrochloric acid in a similar manner to the process described inExample 191.

¹H-NMR (DMSO-d₆) δ: 1.50-1.97 (6H, m), 2.82 (3H, s), 2.91 (3H, s), 2.98(3H, s), 2.83-3.88 (7H, m), 4.30-4.79 (2H, m), 7.37 (2H, d, J=8.8 Hz),7.89 (2H, d, J=8.8 Hz), 8.34 (1H, d, J=8.4 Hz), 8.63 (1H, d, J=8.8 Hz),10.72 (1H, s).

MS (ESI) m/z: 547 (M+H)⁺.

Example 271N¹-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-N²-(pyridin-4-yl)ethanediamidehydrochloride

The title compound was obtained by deprotecting the compound obtained inReferential Example 310 by hydrochloric acid treatment, and condensingthe deprotected compound with lithium2-[(pyridin-4-yl)amino]-2-oxoacetate obtained by hydrolyzing thecompound obtained in Referential Example 261 and then treating thecondensation product with hydrochloric acid in a similar manner to theprocess described in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.40-2.01 (6H, m), 2.79 (3H, s), 3.01 (3H, s),3.00-3.18 (1H, m), 4.02-4.19 (1H, m), 4.45-4.55 (1H, m), 7.09 (1H, s),7.13-7.22 (1H, m), 7.41 (1H, d, J=8.4 Hz), 7.64 (1H, br.s), 8.28 (2H, d,J=6.8 Hz), 8.36 (1H, d, J=8.0 Hz), 8.62 (1H, d, J=8.8 Hz), 8.72 (2H, d,J=6.8 Hz), 11.74 (1H, s), 11.83 (1H, s).

MS (FAB) m/z: 511 (M+H)⁺.

Example 272N¹-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-N²-(pyridin-3-yl)ethanediamidehydrochloride

The title compound was obtained by using methyl2-[(pyridin-3-yl)amino]-2-oxoacetate obtained by condensing3-aminopyridine with methyl 2-chloro-2-oxoacetate in a similar manner tothe process described in Referential Example 242, and the compoundobtained in Referential Example 310 as raw materials in a similar mannerto the process described in Example 271.

¹H-NMR (DMSO-d₆) δ: 1.40-2.05 (6H, m), 2.80 (3H, s), 3.02 (3H, s),2.92-3.15 (1H, m), 4.02-4.17 (1H, m), 4.42-4.58 (1H, m), 7.10 (1H, s),7.12-7.19 (1H, m), 7.40 (1H, d, J=8.4 Hz), 7.62-7.87 (2H, m), 8.36-8.64(4H, m), 9.18 (1H, s), 11.39 (1H, s), 11.79 (1H, s).

MS (FAB) m/z: 511 (M+H)⁺.

Example 273N¹-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-N²-(piperidin-4-yl)ethanediamidehydrochloride

A 4N dioxane solution (8.0 ml) of hydrochloric acid was added to asolution of the compound (400 mg) obtained in Referential Example 389 inethanol (5.0 ml) at room temperature and the mixture was stirred thesame temperature for 5 hours. The solvent was distilled off underreduced pressure, the residue was washed with methylene chloride, andinsoluble matter was filtered and washed to obtain the title compound(320 mg).

¹H-NMR (DMSO-d₆) δ: 1.38-1.92 (10H, m), 2.77 (3H, s), 2.96 (3H, s),2.82-3.35 (6H, m), 3.88-4.10 (2H, m), 4.34-4.43 (1H, m), 7.05 (1H, s),7.11-7.17 (1H, m), 7.38 (1H, d, J=8.8 Hz), 7.65 (1H, s), 8.25 (1H, d,J=8.0 Hz), 8.34 (1H, d, J=7.6 Hz), 8.89 (1H, d, J=8.4 Hz), 11.75 (1H,s).

MS (ESI) m/z: 517 (M+H)⁺.

Example 274N¹-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-N²-(1-methylpiperidin-4-yl)ethanediamidehydrochloride

The title compound was obtained by methylating the compound obtained inExample 273 in a similar manner to the process described in ReferentialExample 9 and treating it with hydrochloric acid.

¹H-NMR (DMSO-d₆) δ: 1.40-2.01 (11H, m), 2.67 (3H, s), 2.79 (3H, s), 2.98(3H, s), 2.85-4.48 (7H, m), 7.07 (1H, s), 7.16 (1H, dd, J=8.8, 2.0 Hz),7.40 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=2.0 Hz), 8.25-8.35 (1H, m), 8.37(1H, d, J=7.6 Hz), 8.90-9.02 (1H, m), 9.82 (1H, br.s), 11.78 (1H, s).

MS (ESI) m/z: 531 (M+H)⁺.

Example 275N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl))-N¹-methylethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 390, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.32-1.97 (6H, m), 2.42-2.51 (1H, m), 2.76 (3H, s),2.91 (3H, s), 2.93 (3H, s), 3.27 (3H, s), 3.00-4.80 (8H, m), 7.45 (1H,br.s), 7.88-7.97 (1H, m), 8.25-8.41 (2H, m), 8.78-8.91 (1H, m).

MS (FAB) m/z: 562 (M+H)⁺.

Example 276N¹-(5-Chloropyrimidin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 391, condensing the hydrolyzate with the compoundobtained in Referential Example 253 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 191.

¹H-NMR (DMSO-d₆) δ: 1.38-2.10 (7H, m), 2.77 (3H, s), 2.90 (3H, s), 2.93(3H, s), 3.04-4.80 (8H, m), 8.60-8.70 (2H, m), 8.82 (2H, s), 9.08 (1H,br.s), 10.64 (1H, s), 11.57 (1H, br.s).

MS (FAB) m/z: 549 (M+H)⁺.

Example 277N¹-(4-Chlorophenyl)-N²-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by reducing the compound obtained inReferential Example 392 in a similar manner to the process described inReferential Example 253, and condensing the reduction product with thecarboxylic acid obtained by hydrolyzing the compound obtained inReferential Example 242 and treating the condensation product withhydrochloric acid in a similar manner to the process described inExample 195.

¹H-NMR (DMSO-d₆) δ: 0.96, 1.02 (3H, each t, J=7.0 Hz), 1.47-1.58 (1H,m), 1.65-1.77 (3H, m), 1.98-2.08 (2H, m), 2.76-2.91 (4H, m), 3.07 (3H,s), 3.19-3.41 (2H, m), 3.98-4.04 (1H, m), 4.42 (1H, br.s), 4.46-4.94(4H, m), 7.41 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz), 8.74-8.80 (1H,m), 9.02 (1H, d, J=7.3 Hz), 10.82 (1H, s), 12.41 (1H, br.s).

MS (FAB) m/z: 547 (M+H)⁺.

Example 278N¹-(5-Bromopyridin-2-yl)-N²-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 392 and the compound obtained in Referential Example262 in a similar manner to the process described in Example 277.

¹H-NMR (DMSO-d₆) δ: 0.90-1.08 (3H, m), 1.40-2.13 (6H, m), 2.70-3.53(13H, m), 3.92-4.08 (1H, m), 4.35-4.47 (1H, m), 7.95 (1H, d, J=8.8 Hz),8.10 (1H, dd, J=8.8, 2.4 Hz), 8.50-8.55 (1H, m), 8.68-8.78 (1H, m),9.12-9.18 (1H, m), 10.26 (1H, s).

MS (FAB) m/z: 592 (M+H)⁺.

Example 279N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained from the compound obtained inReferential Example 392 and the compound obtained in Referential Example243 in a similar manner to the process described in Example 277.

¹H-NMR (DMSO-d₆) δ: [0.95 (t, J=7.0 Hz), 1.01 (t, J=6.8 Hz), 3H],1.45-1.72 (4H, m), 1.96-2.07 (2H, m), 2.74-2.90 (4H, m), 3.06 (3H, s),3.18-3.40 (2H, m), 3.95-4.02 (1H, m), 4.41 (1H, br.s), 4.54-4.90 (4H,m), 8.00 (2H, br.s), 8.45 (1H, s), 8.70-8.75 (1H, m), 9.15 (1H, br.s),10.27 (1H, br.s), 12.29 (1H, br.s).

MS (ESI) m/z: 548 (M+H)⁺.

Example 280N¹-(4-Chloro-3-methoxyphenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 395 with the compound obtained in ReferentialExample 10 and treating the condensation product with hydrochloric acidin a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.46-1.54 (1H, m), 1.67-1.77 (3H, m), 2.01-2.10 (2H,m), 2.79 (3H, s), 2.92-2.98 (7H, m), 3.21 (2H, br.s), 3.49 (1H, br.s),3.69 (1H, br.s), 3.80 (3H, s), 3.98-4.03 (1H, m), 4.42-4.50 (2H, m),4.69 (1H, br.s), 7.37 (1H, d, J=8.7 Hz), 7.48 (1H, dd, J=8.7, 2.2 Hz),7.72 (1H, d, J=2.2 Hz), 8.75 (1H, d, J=7.3 Hz), 9.06 (1H, br.s), 10.77(1H, s), 11.44 (1H, br.s).

MS (FAB) m/z: 577 (M+H)⁺.

Example 281 N¹-(4-Chlorophenyl)-N2((1R*,2R*)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)ethanediamidehydrochloride

The title compound was obtained by hydrolyzing the compound obtained inReferential Example 242, condensing the hydrolyzate with the compoundobtained in Referential Example 62 and then treating the condensationproduct with hydrochloric acid in a similar manner to the processdescribed in Example 195.

¹H-NMR (DMSO-d₆) δ: 1.65-1.73 (4H, m), 1.91-1.96 (2H, m), 2.91 (3H, s),3.15 (2H, br.s), 3.49 (1H, br.s), 3.66 (1H, br.s), 4.32-4.42 (3H, m),4.66 (1H, br.s), 7.40 (2H, d, J=8.9 Hz), 7.84 (2H, d, J=8.9 Hz), 8.92(1H, d, J=8.5 Hz), 9.03 (1H, d, J=8.3 Hz), 10.76 (1H, s), 11.32 (1H,br.s).

MS (FAB) m/z: 462 (M+H)⁺.

Example 282 N¹-(5-Chloropyridin-2-yl)-N2((1R*,2R*)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 62 with the compound obtained in Referential Example266 and then treating the condensation product with hydrochloric acid ina similar manner to the process described in Example 208.

¹H-NMR (DMSO-d₆) δ: 1.71 (4H, br.s), 1.96 (2H, br.s), 2.90 (3H, s), 3.14(1H, br.s), 3.21 (1H, br.s), 3.47 (1H, br.s), 3.68 (1H, br.s), 4.34-4.45(3H, m), 4.66 (1H, br.s), 7.99-8.06 (2H, m), 8.43-8.44 (1H, m), 8.94(1H, d, J=8.3 Hz), 9.20 (1H, d, J=8.5 Hz), 10.20 (1H, br.s), 11.78(1.1H, br.s).

MS (FAB) m/z: 463 (M+H)⁺.

Example 283N¹-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N²-(4-ethynylphenyl)ethanediamide

The title compound was obtained by condensing the compound obtained inReferential Example 252 with the compound obtained in ReferentialExample 397 in a similar manner to the process described in Example 263.

¹H-NMR (CDCl₃) δ: 1.67-2.16 (6H, m), 2.51 (3H, s), 2.76-2.91 (5H, m),2.94 (3H, s), 3.04 (3H, s), 3.07 (1H, s), [3.65 (1H, d, J=15.5 Hz), 3.73(1H, d, J=15.5 Hz) AB pattern], 4.09-4.16 (1H, m), 4.72-4.75 (1H, m),7.42-7.46 (3H, m), 7.58 (2H, d, J=8.5 Hz), 8.02 (1H, d, J=8.1 Hz), 9.36(1H, s).

MS (FAB) m/z: 537 (M+H)⁺.

Example 284N¹-(5-Chloropyrazin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 253 with the compound obtained in ReferentialExample 399 in a similar manner to the process described in ReferentialExample 97 and then treating the condensation product with hydrochloricacid.

¹H-NMR (DMSO-d₆) δ: 1.44-1.52 (1H, m), 1.65-1.77 (3H, m), 2.00-2.10 (2H,m), 2.77 (3H, s), 2.91-2.97 (7H, m), 3.20 (2H, br.s), 3.48 (1H, br.s),3.68 (1H, br.s), 3.97-4.02 (1H, m), 4.40-4.46 (2H, m), 4.68 (1H, br.s),8.64 (1H, d, J=1.2 Hz), 8.70 (1H, d, J=7.3 Hz), 9.02 (1H, s), 9.21 (1H,br.s), 10.91 (1H, br.s), 11.50 (1H, br.s).

MS (FAB) m/z: 549 (M+H)⁺.

Example 285N¹-(4-Chloro-3-nitrophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 253 with the compound obtained in ReferentialExample 400 in a similar manner to the process described in ReferentialExample 97 and then treating the condensation product with hydrochloricacid.

¹H-NMR (DMSO-d₆) δ: 1.44-1.53 (1H, m), 1.66-1.73 (3H, m), 1.97-2.07 (2H,m), 2.77 (3H, s), 2.89-3.05 (7H, m), 3.20 (2H, br.s), 3.55 (2H, br.s),4.00 (1H, br.s), 4.44 (1H, br.s), 4.52 (2H, br.s), 7.75 (1H, d, J=8.8Hz), 8.08 (1H, d, J=8.8 Hz), 8.59 (1H, s), 8.71 (1H, d, J=7.3 Hz), 9.07(1H, d, J=8.0 Hz), 11.24 (1H, s), 11.58 (1H, br.s).

MS (FAB) m/z: 592 (M+H)⁺.

Example 286N¹-(4-Chloro-2-nitrophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 253 with the compound obtained in ReferentialExample 401 and then treating the condensation product with hydrochloricacid in a similar manner to the process described in Example 208.

¹H-NMR (DMSO-d₆) δ: 1.46-1.54 (1H, m), 1.66-1.77 (3H, m), 2.03-2.10 (2H,m), 2.79 (3H, s), 2.90-2.93 (7H, m), 3.17-3.28 (2H, m), 3.49 (1H, br.s),3.68 (1H, br.s), 3.99-4.04 (1H, m), 4.41 (1H, br.s), 4.46 (1H, br.s),4.68 (1H, br.s), 7.89 (1H, d, J=9.0 Hz), 8.20-8.21 (2H, m), 8.73 (1H, d,J=6.4 Hz), 9.28 (1H, br.s), 11.49 (1H, br.s), 11.56 (1H, s).

MS (FAB) m/z: 592 (M+H)⁺.

Example 287N¹-(3-Amino-4-chlorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The compound (236 mg) obtained in Example 285 was dissolved in ethanol(25 ml), and a catalytic amount of Raney nickel was added to stir themixture at room temperature for 17 hours under a hydrogen atmosphere.Thereafter, a catalytic amount of Raney nickel was additionally added tostir the mixture for additional 7 hours. The catalyst was removed byfiltration, and the solvent was distilled off under reduced pressure.The residue was purified by column chromatography on silica gel(methylene chloride:methanol=23:2) to obtain a pale yellow solid (101mg). This product was dissolved in methylene chloride, and a 1N ethanolsolution (360 μl) of hydrochloric acid. The solvent was distilled offunder reduced pressure, a small amount of methanol was added to theresidue, and diethyl ether was added dropwise while irradiating withultrasonic waves to collect precipitate formed. This product was washedwith diethyl ether to obtain the title compound (95 mg).

¹H-NMR (DMSO-d₆) δ: 1.45-1.53 (1H, m), 1.66-1.73 (3H, m), 1.97-2.10 (2H,m), 2.78 (3H, s), 2.91-2.94 (7H, br.s), 3.11-3.19 (1H, m), 3.29 (1H,br.s), 3.48 (1H, br.s), 3.69 (1H, br.s), 3.95-4.02 (1H, m), 4.44 (2H,br.s), 4.68, 4.72 (1H, each br.s), 4.86 (2.5H, br.s), 6.98 (1H, dd,J=8.5, 1.9 Hz), 7.14 (1H, d, J=8.5 Hz), 7.35, 7.38 (1H, each br.s),8.72-8.77 (1H, m), [8.91 (d, J=7.8 Hz), 8.99 (d, J=8.5 Hz), 1H], 10.45,10.47 (1H, each br.s), 11.74 (1H, br.s).

MS (FAB) m/z: 562 (M+H)⁺.

Example 288N¹-(2-Amino-4-chlorophenyl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained from the compound obtained in Example286 in a similar manner to the process described in Example 287.

¹H-NMR (DMSO-d₆) δ: 1.45-1.77 (4H, m), 2.06-2.09 (2H, m), 2.78 (3H, s),2.92 (7H, br.s), 3.12-3.19 (1H, m), 3.26-3.28 (1H, m), 3.48 (1H, br.s),3.70 (1H, br.s), 4.00-4.44 (5.7H, m), 4.70, 4.74 (1H, each br.s),6.63-6.66 (1H, m), 6.85 (1H, br.s), 7.18-7.21 (1H, m), 8.77-8.81 (1H,m), [8.97 (d, J=7.8 Hz), 9.06 (d, J=8.1 Hz), 1H], 9.98 (1H, s), 11.60(1H, br.s).

MS (FAB) m/z: 562 (M+H)⁺.

Example 289N¹-(6-Chloro-4-methylpyridin-3-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 270 with the compound obtained in ReferentialExample 402 and then treating the condensation product with hydrochloricacid in a similar manner to the process described Example 199.

¹H-NMR (DMSO-d₆) δ: 1.45-1.54 (1H, m), 1.65-1.77 (3H, m), 2.02-2.08 (2H,m), 2.22 (3H, s), 2.79 (3H, s), 2.89-2.93 (7H, m), 3.19 (2H, br.s), 3.54(2H, br.s), 3.99-4.04 (1H, m), 4.40-4.42 (1H, m), 4.50 (2H, br.s), 7.49(1H, s), 8.32 (1H, s), 8.75 (1H, d, J=7.1 Hz), 9.09 (1H, d, J=7.3 Hz),10.48 (1H, s), 11.40 (0.9H, br.s).

MS (FAB) m/z: 562 (M+H)⁺.

Example 290N-{(1R,2S,5S)-2-({[(E)-2-(4-Chlorophenyl)diazenyl]carbonyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

After 10% Palladium on carbon (200 mg) was added to a solution of thecompound (700 mg) obtained in Referential Example 252 in tetrahydrofuran(10 ml), and the mixture was stirred at room temperature for 2 daysunder a hydrogen atmosphere, the reaction mixture was filtered, and thecompound obtained in Referential Example 405 (470 mg) was added to asolution of an amine obtained by concentrating the filtrate in formamide(5.0 ml) to stir the mixture at 95° C. for 18 hours. After the reactionmixture was concentrated, and a saturated aqueous solution (50 ml) ofsodium hydrogencarbonate, water (50 ml) and methylene chloride (30 ml)were added to conduct liquid separation, the resultant water layer wasextracted with methylene chloride (2×20 ml). Organic layers werecombined, dried over anhydrous sodium sulfate, concentrated and purifiedby column chromatography on silica gel (methylenechloride:methanol=12:1). This purified product was treated with a 1Nethanol solution of hydrochloric acid to obtain the title compound (100mg).

¹H-NMR (DMSO-d₆) δ: 1.40-1.60 (1H, m), 1.65-2.05 (5H, m), 2.80 (3H, s),2.91 (3H, s), 2.99 (3H, s), 3.00-3.20 (2H, m), 3.20-3.32 (1H, m), 3.43(1H, br.s), 3.69 (1H, br.s), 3.95 (1H, br.s), 4.45 (1H, br.s), 4.60-4.80(2H, m), 7.68 (2H, d, J=8.7 Hz), 7.83 (2H, d, J=8.7 Hz), 8.41 (1H,br.s), 8.68 (1H, d, J=7.6 Hz), 11.40-11.80 (1H, br).

MS (ESI) m/z: 532 (M+H)⁺.

Example 291N-{(1R,2S,5S)-2-({[2-(4-Chlorophenyl)hydrazino]carbonyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by changing the reaction conditions inthe reaction described in Example 290 to conditions that stirring wasconducted at 40° C. for 3 days.

¹H-NMR (DMSO-d₆) δ: 1.30-1.50 (1H, m), 1.50-1.80 (3H, m), 1.80-1.97 (2H,m), 2.76 (3H, s), 2.80-3.05 (2H, m), 2.91 (6H, s), 3.05-3.30 (2H, m),3.47 (2H, br.s), 4.30-4.50 (2H, m), 4.72 (1H, t, J=12.8 Hz), 6.40-6.60(2H, m), 6.55-6.70 (2H, m), 6.95-7.20 (2H, m), 7.88 (1H, d, J=11.3 Hz),8.48-8.65 (1H, m), 11.48-11.80 (1H, br).

MS (ESI) m/z: 534 (M+H)⁺.

Example 292N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 34 with the compound obtained in Referential Example420 and then treating the condensation product with hydrochloric acid ina similar manner to the process described Example 17.

¹H-NMR (DMSO-d₆) δ: 1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 1.95-2.10 (2H,m), 2.78 (3H, s), 2.85-3.00 (4H, m), 3.11 (2H, br s), 3.40-3.55 (2H, m),3.95-4.07 (1H, m), 4.37-4.45 (1H, m), 4.48 (2H, br s), 8.00-8.01 (2H,m), 8.43-8.47 (1H, m), 8.10 (1H, d, J=7.1 Hz), 9.16 (1H, d, J=7.8 Hz),9.43 (2H, br s), 10.27 (1H, s).

MS (FAB) m/z: 534 (M+H)⁺.

Example 293N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(1-hydroxycyclopropyl)carbonyl]piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by condensing the compound obtained inExample 118 with 1-hydroxy-1-cyclopropanecarboxylic acid and thentreating the condensation product with hydrochloric acid in a similarmanner to the process described Example 150.

¹H-NMR (DMSO-d₆) δ: 0.60-0.90 (3H, br), 0.92-1.03 (1H, m), 1.71-1.84(1H, m), 1.85-2.03 (1H, m), 2.91 (3H, s), 3.00-3.80 (7H, m), 4.05-4.80(5H, m), 6.28-6.42 (1H, br), 7.09 (1H, s), 7.18 (1H, dd, J=8.8, 1.5 Hz),7.42 (1H, d, J=8.8 Hz), 7.70 (1H, d, J=1.5 Hz), 8.14-8.29 (1H, br), 8.41(1H, br d, J=7.6 Hz), 11.83 (1H, s).

MS (ESI) m/z: 557 (M+H)⁺.

Example 294N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(1-methoxycyclopropyl)carbonyl]piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by condensing the compound obtained inExample 118 with the compound obtained in Referential Example 409 andthen treating the condensation product with hydrochloric acid in asimilar manner to the process described Example 150.

¹H-NMR (DMSO-d₆) δ: 0.65-1.05 (4H, m), 1.74-1.88 (1H, m), 1.92-2.10 (1H,m), 2.91 (3H, s), 3.00-3.80 (10H, m), 4.05-4.83 (6H, m), 7.08 (1H, s),7.18 (1H, dd, J=8.6, 2.0 Hz), 7.42 (1H, d, J=8.6 Hz), 7.71 (1H, d, J=2.0Hz), 8.08-8.30 (1H, br), 8.41 (1H, br d, J=7.8 Hz), 10.60-10.80 (0.5H,br), 10.85-11.05 (0.5H, br), 11.84 (1H, s).

Example 2957-Chloro-N-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)-3-isoquinolinecarboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 410 with a 4N dioxane solution of hydrochloric acidto deprotect it, condensing the deprotected compound with the compoundobtained in Referential Example 10 and then subjecting the condensationproduct to a hydrochloric acid treatment again in a similar manner tothe process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.60-1.80 (1H, m), 2.13-2.38 (1H, m), 2.90 (3H, s),3.00-3.87 (10H, m), 3.89-4.10 (2H, m), 4.15-4.58 (4H, m), 4.60-4.78 (1H,m), 7.89 (1H, d, J=8.8 Hz), 8.25 (1H, d, J=8.8 Hz), 8.37 (1H, s), 8.61(1H, s), 8.70-8.95 (1H, m), 9.05-9.29 (1H, m), 9.36 (1H, s), 11.20-11.40(0.5H, br), 11.45-11.65 (0.5H, br).

MS (ESI) m/z: 557 (M+H)⁺.

Example 296N¹-(4-chloro-3-fluorophenyl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 411 with a 4N dioxane solution of hydrochloric acidto deprotect it, condensing the deprotected compound with the compoundobtained in Referential Example 10 and then subjecting the condensationproduct to a hydrochloric acid treatment again in a similar manner tothe process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.60-1.72 (1H, m), 1.98-2.21 (1H, m), 2.91 (3H, s),3.00-3.52 (9H, m), 3.56-4.05 (3H, m), 4.08-4.50 (4H, m), 4.60-4.78 (1H,br), 7.56 (1H, t, J=8.8 Hz), 7.70 (1H, d, J=9.0 Hz), 7.91 (1H, dd,J=8.8, 2.3 Hz), 8.50-8.72 (1H, m), 9.15-9.35 (1H, m), 11.02 (1H, s),11.15-11.33 (0.5H, br), 11.35-11.50 (0.5H, br).

MS (FAB) m/z: 567 (M+H)⁺.

Example 297N¹-(5-chloro-2-thienyl)-N²-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)ethanediamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 412 with a 4N dioxane solution of hydrochloric acidto deprotect it, condensing the deprotected compound with the compoundobtained in Referential Example 10 and then subjecting the condensationproduct to a hydrochloric acid treatment again in a similar manner tothe process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.60-1.73 (1H, m), 1.96-2.19 (1H, m), 2.91 (3H, s),3.04-3.54 (9H, m), 3.60-4.05 (3H, m), 4.07-4.34 (3H, m), 4.35-4.54 (1H,br), 4.60-4.80 (1H, br), 6.89 (1H, d, J=4.2 Hz), 6.93 (1H, d, J=4.2 Hz),8.48-8.70 (1H, m), 9.18-9.40 (1H, m), 12.31 (1H, s).

MS (ESI) m/z: 555 (M+H)⁺.

Example 298N-{(1R,2S,5S)-2-{[2-(4-Chlorophenoxy)acetyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by reducing the compound obtained inReferential Example 252, condensing the reduction product withp-chlorophenoxyacetic acid and treating the condensation product withhydrochloric acid in a similar manner to the process described inExample 223.

¹H-NMR (DMSO-d₆) δ: 1.35-1.47 (1H, m), 1.55-1.90 (5H, m), 2.77 (3H, s),2.92 (3H, s), 2.96 (3H, s), 2.98-3.10 (1H, m), 3.10-3.80 (3H, m),3.85-3.95 (1H, m), 4.35-4.50 (4H, m), 4.50-4.80 (1H, br), 6.85 (2H, d,J=8.5 Hz), 7.15-7.35 (1H, br), 7.88-8.03 (1H, br), 8.46 (1H, d, J=8.8Hz), 11.30-11.65 (1H, br).

MS (FAB) m/z: 534 (M+H)⁺.

Example 2997-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)-3-isoquinolinecarboxamidehydrochloride

The title compound was obtained by condensing the lithium salt of thecarboxylic acid obtained by hydrolyzing the compound obtained inReferential Example 413 with a compound obtained by deprotecting thecompound obtained in Referential Example 146 by an acid treatment andtreating the condensation product with hydrochloric acid.

¹H-NMR (DMSO-d₆) δ: 1.00-1.11 (2H, m), 1.45-1.60 (1H, m), 1.65-1.85 (1H,m), 1.95-2.06 (1H, m), 2.10-2.24 (1H, m), 2.78 (3H, s), 2.87-3.02 (1H,m), 2.94 (3H, s), 3.88 (3H, s), 4.16-4.27 (1H, m), 4.45-4.56 (1H, m),7.03 (1H, s), 7.55 (1H, s), 7.87 (1H, br d, J=8.3 Hz), 8.24 (1H, br d,J=8.8 Hz), 8.33 (1H, s), 8.59 (1H, s), 8.85 (1H, br d, J=7.6 Hz), 9.01(1H, br d, J=7.8 Hz), 9.28 (1H, s).

MS (ESI) m/z: 539 (M+H)⁺.

Example 300N-{(1R,2S,5S)-2-{[(6-Chloro-4-oxo-4H-chromen-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by condensing a compound obtained bytreating the compound in Referential Example 417 with a 4N dioxanesolution of hydrochloric acid with the compound obtained in ReferentialExample 10 and then treating the condensation product with hydrochloricacid in a similar manner to the process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.40-1.53 (1H, m), 1.67-2.04 (5H, m), 2.40-2.53 (1H,m), 2.80 (3H, s), 2.92 (3H, s), 3.01 (3H, s), 3.09-3.22 (3H, m),3.66-3.77 (1H, m), 4.01-4.10 (1H, m), 4.34-4.49 (1H, m), 4.58-4.76 (2H,m), 6.80 (1H, d, J=4.9 Hz), 7.59-7.70 (1H, m), 7.90-8.00 (1H, m), 7.96(1H, s), 8.52-8.60 (1H, m), 8.80-8.90 (1H, m), 11.10-11.25 (0.5H, br),11.40-11.55 (0.5H, br).

MS (ESI) m/z: 572 (M+H)⁺.

Example 3017-Chloro-N-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)-3-cinnolinecarboxamidehydrochloride

The title compound was obtained by condensing a compound obtained bytreating the compound obtained in Referential Example 418 with a 4Ndioxane solution of hydrochloric acid with the compound obtained inReferential Example 10 and then treating the condensation product withhydrochloric acid in a similar manner to the process described inExample 219.

¹H-NMR (DMSO-d₆) δ: 1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s),3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82 (7H, m), 3.88-4.80 (5H, m),7.09 (1H, d, J=9.0 Hz), 7.17 (1H, dd, J=8.8, 1.9 Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, d, J=1.9 Hz), 8.29 (1H, br s), 8.40-8.50 (1H, m),11.20-11.50 (1H, br m), 11.85 (1H, s).

MS (ESI) m/z: 558 (M+H)⁺.

Example 302N¹-(5-Chloropyridin-2-yl)-N²-(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidehydrochloride

The title compound was obtained by deprotecting the compound obtained inReferential Example 421 with hydrochloric acid, methylating thedeprotected compound in a similar manner to the process described inExample 18 and treating it with hydrochloric acid.

¹H-NMR (DMSO-d₆) δ: 1.42-1.58 (1H, m), 1.59-1.80 (3H, m), 1.83-1.95 (1H,m), 1.97-2.10 (1H, m), 2.78 (3H, s), 2.89 (3H, s), 2.96 (3H, s),3.00-3.10 (1H, m), 3.10-3.20 (2H, m), 3.45-3.80 (1H, m), 3.90-4.00 (2H,m), 4.00-4.50 (3H, m), 7.77 (1H, s), 7.95-8.05 (3H, m), 8.44 (1H, t,J=1.6 Hz), 8.90 (1H, d, J=8.6 Hz), 10.25 (1H, s), 11.12 (1H, br s).

MS (ESI) m/z: 547 (M+H)⁺.

Example 303N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]aminocyclohexyl)ethanediamidehydrochloride

The title compound was obtained by condensing the compound obtained inReferential Example 418 with the compound obtained in ReferentialExample 420 and then treating the condensation product with hydrochloricacid in a similar manner to the process described in Example 2.

¹H-NMR (DMSO-d₆) δ: 1.30-1.40 (6H, m), 1.38-1.58 (1H, m), 1.59-1.82 (3H,m), 1.95-2.13 (2H, m), 2.40-2.65 (1H, m), 2.49 (3H, s), 2.87-3.55 (4H,m), 2.49 (3H, s), 3.60-3.82 (2H, m), 3.93-4.04 (1H, m), 4.37-4.55 (2H,m), 4.55-4.72 (1H, m), 7.94-8.10 (2H, m), 8.43 (1H, s), 8.64-8.77 (1H,m), 9.12 (½H, d, J=7.8 Hz), 9.24 (½H, d, J=7.8 Hz), 10.22 (½H, s), 10.26(½H, s), 11.25 (½H, br s), 11.44 (½H, br s).

MS (FAB) m/z: 578 (M+H)⁺.

Example 304N-((1R,2S,5S)-5-[(Dimethylamino)carbonyl]-2-{[2-(4-fluoroanilino)-2-oxoethanethioyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 424 with hydrochloric acid to deprotect it,condensing the deprotected compound with the compound obtained inReferential Example 10 and then subjecting the condensation product to ahydrochloric acid treatment again in a similar manner to the processdescribed in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.45-1.60 (1H, m), 1.60-1.80 (3H, m), 2.00-2.10 (1H,m), 2.20-2.35 (1H, m), 2.79 (3H, s), 2.93 (3H, s), 2.95 (3H, s),2.95-3.10 (1H, m), 3.10-3.30 (2H, m), 3.40-3.60 (1H, m), 3.60-3.80 (1H,m), 4.35-4.50 (1H, m), 4.50-4.60 (1H, m), 4.60-4.80 (2H, m), 7.20 (2H,t, J=8.8 Hz), 7.77 (2H, dd, J=9.0, 5.1 Hz), 8.80 (1H, br), 10.42 (1H,s), 10.93 (1H, br), 11.28 (1H, br).

MS (ESI) m/z: 547 (M+H)⁺.

Example 305N-[(1R,2S,5S)-5-[(Dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)amino]-2-oxoethanethioyl}amino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 427 with hydrochloric acid to deprotect it,condensing the deprotected compound with the compound obtained inReferential Example 10 and then subjecting the condensation product to ahydrochloric acid treatment again in a similar manner to the processdescribed in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.43-1.57 (1H, m), 1.64-1.87 (3H, m), 2.00 (1H, brs), 2.17-2.34 (1H, m), 2.78 (3H, s), 2.90 (3H, s), 2.95 (3H, s),2.95-3.10 (1H, m), 3.10-3.30 (2H, m), 3.40-3.60 (1H, m), 3.68 (1H, brs), 4.44 (1H, br s), 4.45-4.56 (1H, m), 4.60-4.73 (2H, m), 7.80-7.90(1H, m), 8.08 (1H, dd, J=9.1, 3.9 Hz), 8.41 (1H, d, J=2.9 Hz), 8.79 (1H,d, J=6.6 Hz), 10.49 (1H, s), 11.07 (1H, br s), 11.69 (1H, br).

MS (ESI) m/z: 548 (M+H)⁺.

Example 306N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5H-pyrrolo[3,4-d]thiazole-2-carboxamide

The title compound was obtained by treating the compound obtained inReferential Example 428 with hydrochloric acid to deprotect it and thencondensing the deprotected compound with the compound obtained inReferential Example 293 in a similar manner to the process described inExample 219.

¹H-NMR (DMSO-d₆) δ: 1.45-1.58 (1H, m), 1.63-1.73 (2H, m), 1.73-1.87 (2H,m), 2.00-2.10 (1H, m), 2.20-2.35 (1H, m), 2.79 (3H, s), 2.95 (3H, s),2.96-3.10 (1H, m), 3.89 (3H, s), 4.48-4.58 (1H, m), 4.60-4.70 (1H, m),7.05 (1H, d, J=1.7 Hz), 7.55 (1H, d, J=1.7 Hz), 8.00 (1H, dd, J=8.9, 2.4Hz), 8.05 (1H, d, J=8.9 Hz), 8.44 (1H, d, J=2.4 Hz), 8.71 (1H, d, J=7.3Hz), 10.57 (1H, s), 11.13 (1H, d, J=7.8 Hz).

MS (FAB) m/z: 548 (M+H)⁺.

Example 307N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamidehydrochloride

The title compound was obtained by treating the compound obtained inReferential Example 428 with hydrochloric acid to deprotect it,condensing the deprotected compound with the compound obtained inReferential Example 293 under an argon atmosphere and then subjectingthe condensation product to a hydrochloric acid treatment again in asimilar manner to the process described in Example 219.

¹H-NMR (DMSO-d₆) δ: 1.42-1.58 (1H, m), 1.65-1.87 (3H, m), 1.97-2.10 (1H,m), 2.17-2.30 (1H, m), 2.80 (3H, s), 2.96 (3H, s), 2.98-3.10 (1H, m),3.07 (3H, s), 4.30-5.00 (6H, m), 8.00-8.10 (1H, m), 8.46 (1H, d, J=2.4Hz), 8.79 (1H, t, J=7.3 Hz), 10.54 (1H, s), 11.04 (1H, d, J=7.8 Hz),12.24 (1H, br s).

MS (ESI) m/z: 550 (M+H)⁺.

Example 308N¹-(5-Chloropyridin-2-yl)-N²-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-({[6-(dimethylamino)-4,5,6,7-tetrahydrobenzothiazol-2-yl]carbonyl}amino)cyclohexyl]ethanediamide

The title compound was obtained by deprotecting the compound obtained inReferential Example 431 with hydrochloric acid, methylating thedeprotected compound in a similar manner to the process described inExample 18 and treating it with hydrochloric acid.

¹H-NMR (DMSO-d₆) δ: 1.42-1.58 (1H, m), 1.59-1.80 (3H, m), 1.90-2.12 (3H,m), 2.30-2.45 (1H, m), 2.70-3.00 (11H, m), 2.92 (3H, s), 3.00-3.20 (2H,m), 3.25-3.45 (1H, m), 3.63-3.80 (1H, m), 3.88-4.02 (1H, m), 4.35-4.47(1H, m), 8.02 (1H, s), 8.42-8.55 (1H, m), 8.60-8.68 (1H, m), 8.93 (1H,dd, J=14.5, 8.2 Hz), 9.19 (1H, dd, J=17.7, 8.2 Hz), 10.28 (1H, s), 10.91(1H, br s).

MS (ESI) m/z: 576 (M+H)⁺.

Example 309N-{(1R,2S,5S)-2-[({[(4-Chlorophenyl)sulfonyl]amino}carbonyl)amino]-5[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamidehydrochloride

4-Chlorophenylsulfonyl isocyanate (148 μl) was added to a solution ofthe compound (328.0 mg) obtained in Referential Example 253 in methylenechloride (10 ml), and the mixture was stirred at room temperature for 24hours. The solvent was distilled off under reduced pressure, and residuewas purified by preparative thin-layer column chromatography on silicagel (methylene chloride:methanol=9:1). The thus-obtained product wasdissolved in ethanol (2 ml) and methylene chloride (2 ml), and a 1Nethanol solution (0.25 ml) of hydrochloric acid was added to stir themixture at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and the residue was solidified withdiethyl ether to obtain the title compound (104.3 mg).

¹H-NMR (DMSO-d₆) δ: 1.25-1.45 (1H, m), 1.45-1.80 (5H, m), 2.76 (3H, s),2.94 (3H, s), 2.97 (3H, s), 3.00-3.80 (6H, m), 4.35-4.85 (3H, m), 6.53(1H, brs), 7.66 (2H, d, J=8.5 Hz), 7.86 (2H, d, J=8.5 Hz), 8.50-8.82(1H, m), 10.64 (1H, br s), 11.10-11.80 (1H, br).

MS (ESI) m/z: 583 (M+H)⁺.

Example 310N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide

The title compound was obtained from the compound obtained inReferential Example 435 and the compound obtained in Referential Example10 in a similar manner to Example 2.

¹H-NMR (CDCl₃) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s),2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69(1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.07-4.15 (1H, m),4.66-4.72 (1H, m), 7.40 (1H, d, J=8.8, 0.6 Hz), 7.68 (1H, dd, J=8.8, 2.4Hz), 8.03 (1H, d, J=7.8 Hz), 8.16 (1H, dd, J=8.8, 0.6 Hz), 8.30 (1H, dd,J=2.4, 0.6 Hz), 9.72 (1H, s).

MS (ESI) m/z: 548 (M+H)⁺.

Example 311N¹-(5-Chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidep-toluenesulfonate monohydrate

The compound (6.2 g) obtained in Example 310 is dissolved in methylenechloride (120 ml), a 1 mol/L ethanol solution (11.28 ml) ofp-toluenesulfonic acid was added to the solution, and the solvent wasdistilled off. Ethanol (95 ml) containing 15% water was added to theresidue, and the mixture was stirred at 60° C. to dissolve it. Thesolution was then cooled to room temperature and stirred for a day.Crystals deposited were collected by filtration, washed with ethanol anddried at room temperature for 2 hours under reduced pressure to obtainthe title compound (7.4 g).

¹H-NMR (DMSO-d₆) δ: 1.45-1.54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H,m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99(3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m),4.43-4.80 (3H, m), 7.11 (2H, d, J=7.8 Hz), 7.46 (2H, d, J=8.2 Hz), 8.01(2H, d, J=1.8 Hz), 8.46 (1H, t, J=1.8 Hz), 8.75 (1H, d, J=6.9 Hz),9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s).

MS (ESI) m/z: 548 (M+H)⁺.

Elemental analysis: C₂₄H₃₀ClN₇O₄S.C₇H₈O₃S.H₂O.

Calculated: C, 50.43; H, 5.46; N, 13.28; Cl, 4.80; S, 8.69.

Found: C, 50.25; H, 5.36; N, 13.32; Cl, 4.93; S, 8.79.

mp (decomposed): 245˜248° C.

Test Example 1 Determination of Human FXa-Inhibiting Effect (IC₅₀ Value)

5% DMSO solutions (10 μl) of each test compound, the concentrations ofwhich were suitably set stepwise, Tris buffer (100 mM Tris, 200 mMpotassium chloride, 0.2% BSA, pH 7.4) (40 μl) and 0.0625 U/ml human FXa(Enzyme Research Laboratories, Inc., dissolved and diluted with Trisbuffer) (10 μl) were respectively put in wells of a 96-well microplate,and a 750 μM aqueous solution (40 μl) of S-2222 (Chromogenix Co.) wasadded. Absorbance at 405 nm was measured for 10 minutes at roomtemperature to determine an increase in absorbance (ΔOD/min). As acontrol, Tris buffer was used in place of the test compound.

The percent inhibition (%) calculated using the following equation atthe final concentration of the test compound and the final concentrationof the test compound were plotted on the axis of ordinate and the axisof abscissa of logarithmic normal probability paper, respectively, todetermine the 50% inhibition concentration (IC₅₀ value).

Percent inhibition (%)=[1−(ΔOD/min of test compound)÷(ΔOD/min ofcontrol)]×100

(Result)

In Table 1, it is demonstrated that the compounds according to thepresent invention have a potent FXa-inhibiting effect.

TABLE 1 Human FXa- inhibiting effect Compound (IC₅₀): nM Ex. 3 86 Ex. 783 Ex. 11 92 Ex. 54 4.2 Ex. 62 3.5 Ex. 63 2.5 Ex. 74 1.4 Ex. 101 26 Ex.130 4.5 Ex. 138 4.4 Ex. 143 5.8 Ex. 164 4.8 Ex. 191 1.2 Ex. 192 2.0 Ex.194 5.0 Ex. 204 1.5 Ex. 246 3.1 Ex. 247 1.9 Ex. 248 5.4

Test Example 2 Determination of Anti-FXa Activity in Rat Plasma afterOral Administration (A) Administration and Blood Collection:

A drug solution (1 mg/ml) obtained by dissolving or suspending a testcompound (10 mg) in 0.5% methyl cellulose (MC) was orally administeredto rats (10 ml/kg). After 0.5, 1, 2 and 4 hours from the drugadministration, the blood (0.5 ml) was collected through the jugularvein using a syringe which is containing a 3.13% (w/v) aqueous solution(50 μl) of trisodium citrate dihydrate (amount of blood collected: 0.45ml). For rats of a control group, the same blood collection wasconducted after a 0.5% MC solution was administered. Each blood samplewas centrifuged at 1500×g for 10 minutes at 4° C. to separate plasma,and the plasma was preserved at −40° C. until it was used in thefollowing determination of anti-FXa activity in plasma.

(B) Determination of FXa-Inhibiting Activity in Plasma:

In the determination of anti-FXa activity in plasma, S-2222 was used asa substrate. Tris buffer (100 mM Tris, 200 mM potassium chloride, 0.2%BSA, pH 7.4) (5456 μl), human FXa (2.5 U/ml, 44 μl) and water (550 μl)were mixed. The resultant human FXa solution was used in the followingtest.

Rat plasma (5 μl) obtained in accordance with the procedure (A)described above was put in wells of a 96-well microplate, and theabove-described human FXa solution (55 μl) and a 750 μM aqueous solution(40 μl) of S-2222 were sequentially added. Immediately after that,absorbance at 405 nm was measured at room temperature by means of aspectrophotometer SPECTRAmax 340 or 190 (Molecular Devices Co., U.S.A.),thereby determining a rate of reaction (ΔOD/min).

The anti-FXa activity, i.e., percent inhibition (%) was calculated inaccordance with the following equation:

Percent inhibition (%)=[1−(ΔOD/min of sample)÷(average value of ΔOD/minof the control group)]×100

(Result)

The compounds described in Examples 63, 191, 192, 194 and 204 exhibiteda potent FXa-inhibiting activity of 62 to 96% at an oral dose of 10mg/kg.

INDUSTRIAL APPLICABILITY

The cyclicdiamine derivatives according to the present invention exhibita potent inhibitory effect on activated blood coagulation factor X andare useful as medicines, activated blood coagulation factor Xinhibitors, anticoagulants, agents for preventing and/or treatingthrombosis or embolism, agents for preventing and/or treating thromboticdisease and agents for preventing and/or treating cerebral infarction,cerebral embolism, myocardial infarction, angina pectoris, pulmonaryinfarction, pulmonary embolism, Buerger's disease, deep venousthrombosis, disseminated intravascular coagulation syndrome, thrombusformation after valve or joint replacement, thrombus formation andreocclusion after angioplasty, systemic inflammatory response syndrome(SIRS), multiple organ dysfunction syndrome (MODS), thrombus formationduring extracorporeal circulation, or blood clotting upon blood drawing.

1. A composition comprising a pharmaceutically acceptable carrier andN¹-(5-chloropyridin-2-yl)N²-(4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetralhydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide,represented by Formula (I), or a salt thereof:


2. A composition comprising a pharmaceutically acceptable carrier andN¹-(5-chloropyridin-2-yl)-N²-(4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidep-toluenesulfonate, represented by Formula (II):


3. A composition comprising a pharmaceLitically acceptable carrier andN¹-(5-chloropyridin-2-yl)-N²-(4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidep-toluenesulfonate monohydrate, represented by Formula (III):


4. A composition comprising a pharmaceutically acceptable carrier andN¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide,represented by Formula (IV), or a salt thereof:


5. A composition comprising a pharmaceutically acceptable carrier andN¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]aminocyclohexyl)ethanediamide p-toluenesulfonate, represented by Formula (V):


6. A composition comprising a pharmaceutically acceptable carrier andN¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamidep-toluenesulfonate monohydrate, represented by Formula (VI):